Prussians besieged Teutonic castles and managed to capture all except for Elbing (Elbląg) and Balga in the eastern regions of Natangia, Barta and Warmia; Thorn (Toruń), Culm (Chełmno), and Rehden (Radzyń Chełmiński) in the western parts. In December 1242, the Knights were able to capture Sartowice, Swantopolk's castle on the banks of the Vistula. The ensuing five-week siege of Sartowice failed to recapture the fortress and Swantopolk lost 900 men. In the spring of 1243, Swantopolk also lost the castle at Nakel (Nakło nad Notecią), which dominated trade on the Noteć River. In the face of these losses, the duke was forced to make short-lived truce. In the summer of 1243, Prussians with Sudovian help raided the Culmerland (Chełmno Land) and, on their way back, defeated the pursuing Teutonic Knights on June 15 on the banks of the Osa River. Some 400 Teutonic soldiers perished, including their marshal. Swantopolk, encouraged by the defeat, gathered an army of 2,000 men and unsuccessfully besieged Culm (Chełmno).

On August 29, 1261 Jacob of Liège, who negotiated the Treaty of Christburg after the first uprising, was elected as Pope Urban IV. He, having an inside scope on events in Prussia, was especially favourable to the Teutonic Knights and issued 22 papal bulls in three years of his papacy calling for reinforcements to the Knights. However, the reinforcements were slow to come as dukes of Poland and Germany were preoccupied with their own disputes and the Livonian Order was fighting the Semigallian uprising.The first reinforcement to the Teutonic forces arrived in early 1261, but was wiped out on January 21, 1261 by Herkus Monte in the Battle of Pokarwis. In January 1262 reinforcements arrived from the Rhineland, led by Wilhelm VII, Duke of Jülich, who was obliged by Pope Alexander IV to fulfil his crusader duties in Prussia. This army broke the Siege of Königsberg but as soon as the army returned home, the Sambians resumed the siege and were reinforced by Herkus Monte and his Natangians. Herkus was later injured and the Natangians retreated, leaving the Sambians unable to stop supplies reaching the castle and the siege eventually failed. Prussians were more successful capturing castles deeper into the Prussian territory (with an exception of Wehlau, now Znamensk), and the Knights were left only with strongholds in Balga, Elbing, Culm , Thorn, and Königsberg. Most castles fell in 1262-1263, and Bartenstein fell in 1264. The Prussians destroyed captured forts instead of using them for their own defence, so the end of successful sieges meant that large Prussian forces did not have to stay near their home and were then free to operate in other parts of Prussia,raiding the Culmerland and Kuyavia.

A recovered Herkus Monte raided Culmerland with a large force and took many prisoners in 1263. On his way back to Natangia, Herkus and his men were confronted by a contingent of their enemies. In the Battle of Löbau that ensued, Prussians killed forty knights, including the Master and the Marshal. The Prussians also received help from Lithuanians and Sudovians. In summer of 1262 Treniota and Shvarn attacked Masovia, killing Duke Siemowit I, and raided Culmerland, provoking Pogesanians to join the uprising. However, assassination of Mindaugas and subsequent dynastic fights prevented Lithuanians from further campaigns. Skalmantas, leader of Sudovians, raided Culm (Chełmno) in 1263 and in 1265. The year of 1265 was the turning point in the uprising: more substantial reinforcements for the Teutonic Knights finally started arriving in Prussia and Sambia gave up the fight. Teutonic castles in Königsberg and Wehlau on the Pregel River cut off the region from the rest of Prussia. Supplies to Königsberg were brought by sea, and the castle served as the basis for raids in surrounding Samland (Sambia). The Livonian Order sent troops to Königsberg and the joint forces defeated the Sambians in a decisive battle forcing them to surrender. In 1265 reinforcements arrived from Germany: armies of Duke Albrecht of Braunschweig and Margrave Albert of Meissen arrived in Prussia, but were unable to achieve much. In 1266 Otto III and John I, co-rulers of Brandenburg, built a castle in the Natangian lands between Balga and Königsberg and named it Brandenburg (since 1945 Ushakovo). Due to bad weather they did not organize campaigns into Prussian lands. When the Dukes returned home, Brandenburg was captured by Glappe and his Warmians.The very next year Otto returned to rebuild the castle. However, both John and Otto died before the end of 1267, and Otto's son was killed in a tournament. Subsequent Dukes of Brandenburg were not as supportive of the Knights. In 1266 Duke Swantopolk, the supporter of the Prussians during the First Uprising, died and his sons Mestwin and Warcisław briefly joined the Prussians in the uprising. In 1267 King Ottokar II of Bohemia, who already participated in the Prussian Crusade in 1254 and who was promised by Pope Urban IV all Prussian lands he could conquer, finally arrived in Prussia. His only achievement was forcing Duke Mestwin to reconcile with the Teutonic Knights. His large army was unable to campaign due to an early thaw: heavily armed knights could hardly fight during the wet and swampy spring season.

The warfare with the Prussians relied on guerilla raids in the border regions. Small groups of men, a dozen to a hundred, made quick raids on farms, villages, border posts, etc. This was a positional warfare where neither side could defeat the other, but the Teutonic Knights relied on future reinforcements from Germany and Europe, while Prussians were draining their local resources. After the massacre of surrendered Teutonic soldiers in the Battle of Krücken in 1249, the Knights refused to negotiate with the Prussians. The Prussians were also unable to coordinate their efforts and develop a common strategy: while each clan had its own leader, there was no one to lead all the clans. The Natangians had to watch for attacks from Balga, Brandenburg, Wehlau, and Königsberg while the Warmians were threatened by garrisons at Christburg and Elbing. This way only Diwane and his Bartians were able to continue the war in the west.The major Prussian offensive was organized in 1271 together with Linka, leader of the Pogesanians. The Bartian infantry and Pogesanians besieged a border castle, but were fended off by the Knights from Christburg. The Prussians who managed to escape joined their cavalry while the Knights set up a camp on the opposite bank of the Dargune River (Dzierzgoń River), blocking the route home. When Christians retired for the night, one half of the Prussian army crossed the river in a distance, in order to attack the Knights from the rear, while the other half charged straight across the river. The Knights were encircled. The Battle of Paganstin saw twelve knights and 500 men killed. The Prussians immediately assaulted Christburg and almost captured it. The Prussians were still looting the surrounding area when cavalry from Elbing arrived. Many of the Prussian infantry perished while cavalry escaped. Despite these losses, Diwane was soon back and blocked roads leading to Christburg hoping to starve the castle. Diwane was killed during a siege of a small post at Schönsee (Wąbrzeźno) in 1273.

In the winter of 1271-1272 reinforcements arrived from Meissen, led by Count Dietrich II. The army invaded Natangia and besieged an unnamed Natangian castle. While the assault claimed 150 lives of the crusaders, most of Notangian resistance was broken and the region was decimated. Herkus Monte, with a small group of his followers, was forced to withdraw to the forests of southern Prussia. Within a year he was finally captured and hanged. The last Prussian leader, Glappe of Warmians, was also hanged when his siege campaign on Brandenburg (now Ushakovo) was attacked from the rear. The last tribe standing were the Pogesanians, who made a surprise raid into Elbing and ambushed its garrison. In 1274 the Knights made a great expedition to avenge this raid, capturing the rebel headquarters at Heilsberg (Lidzbark Warmiński) and ending the uprising. The Knights proceeded to rebuild and strengthen castles destroyed by the Prussians. A number of Prussians escaped either to Sudovia or to Lithuania, or were resettled by the Knights. Many free peasants were made into serfs. Local nobles had to convert and give hostages, and only a few of them were granted privileges to retain their noble status. From 1274 to 1283 the Teutonic Knights conquered Skalvians, Nadruvians, and Sudovians/Yotvingians. After the Great Uprising, the Prussians rose a number of times against the Knights, but these uprisings were much smaller in scale and posed no real danger to the Teutonic Knights, who could concentrate on further conquests. The number of uprisings varies from three to two. They were suppressed within a year or two and showed exhaustion and division of the Prussian tribes. The third uprising in 1276 was provoked by Skalmantas, leader of the Sudovians, who successfully raided Teutonic lands. The next year he, with help from the Lithuanians, led 4,000 men into the Culmerland (Chełmno Land). The uprising failed to spread after Theodoric, vogt of Sambia, convinced the Sambians not to join the insurrection; Natangians and Warmians had also accepted baptism and promised their loyalty to the Knights. The Pogesanians alone continued the fight and were crushed. Survivors with their Bartian chief escaped to Hrodna in the Grand Duchy of Lithuania where they joined some of the Bartians, Skalvians, and all of the Nadruvians, who fled there after the Great Uprising.

The last two Prussian attempts to rid itself of the Teutonic rule were made relying on the foreign powers who were enemies of the Knights. The first one in 1286, also known as the fourth uprising, depended upon help from the Duke of Rügen, the grandson of Swantopolk. The plot was soon revealed and the Bartians and Pogesanians suffered the consequences. In 1295 the last uprising was limited to Natangia and Sambia and depended upon help from Vytenis, Grand Duke of Lithuania. The rebels captured Bartenstein (Bartoszyce) by surprise and plundered as far as Königsberg, but were never a serious threat. By that time Prussian nobility was already baptized and pro-Teutonic to the extent that peasants killed them first before attacking the Knights. This last attempt effectively ended the Prussian Crusade and the Knights concentrated on conquering Samogitia and Lithuania. Lithuanian historians note that fierce resistance by the Prussians won time for the young Lithuanian state to mature and strengthen so it could withstand the hundred-year crusade, culminating in the 1410 Battle of Grunwald, with minimal territorial losses. The Prussian lands were repopulated by colonists from Germany, who after the 16th century eventually outnumbered the natives. It is estimated that around 1400 Prussians numbered 100,000 and comprised about half of the total population in Prussia. The Prussians were subject to Germanization and assimilation and eventually became extinct sometime after the 16th century. It is believed that the Prussian language became extinct sometime at the beginning of the 18th century.