The Teutonic Knights undertook several important missions in the Holy Land. In 1220, they acquired Montfort (Starkenberg), northeast of Acre, a castle, which defended the route between Jerusalem and the Mediterranean Sea. It became the seat of the Grand Masters in 1229, but was lost to the Muslims in 1271. In 1260, the Teutonic Knights took responsiblity for defense of the territory to the immediate north of the fortress city of Acre but were driven out in May 1263 in the Battle of Sidon. After the Muslim victory at Acre in 1291, the Teutonic Knights officially relocated to Europe, first to Venice and then Prussia in 1309. Before this catastrophic defeat drove crusaders, military orders and European rulers from the Holy Land, the Teutonic Knights were active in central Europe, Prussia and the Baltic states. In 1211, the Teutonic Order moved to Transylvania to help defend Hungary against the Cumans. They were expelled in 1225 after allegedly attempting to place themselves under Papal instead of Hungarian sovereignty.

The Northern Crusades were intensified with overt imperialistic objectives for the Teutonic Knights in Prussia and the Baltic states. In 1226, Konrad I, Duke of Masovia in west-central Poland, appealed to the Knights to defend his borders and subdue the pagan Baltic Prussians. With the Golden Bull of Rimini in 1226, Emperor Frederick II bestowed on the Order a special privilege for the conquest and possession of Prussia. The Northern Crusades to convert pagan tribes officially began when Grand Master Hermann von Salza and Duke Konrad I of Masovia undertook a joint invasion of Prussia in 1230 to Christianise the Old Prussians. The small military Order of Dobrzyń established by Konrad was absorbed by the Teutonic Knights in 1235. The Teutonic Knight's conquest of Prussia was brutal. The Old Prussians fought fiercely, were not subdued until 1260 and uprisings continued until 1283. Many of the Old Prussian nobility emigrated, some in the lower classes agreed to baptism. "By 1284, the Teutonic Knights fully subjugate the Prussians, who eventually become extinct as a people and are assimilated by Germans, Poles and Lithuanians." The Teutonic Order adopted the name Prussians for themselves. The native population was decimated and immigration from the German Nations and Masovia was encouraged. Knights were assured that land conquered would remain their own, the legal basis for a Teutonic Order sovereign state had been established. The Order ruled Prussia under charters issued by the Pope and the Holy Roman Emperor as a sovereign monastic state, as did the Knights Hospitallers in Rhodes and later in Malta. The great castle of Koningsberg was built in 1255. Marienbourg in Pomerania was the castle fortress where the Teutonic Knights made their headquarters by 1309. It became a court for chivalry, the late chivalry that sought adventure about all. Marienbourg was also a center for letters and learning. Knights came from afar including Blind King John of Bohemia and Henry of Bolingbrook from England.

The Teutonic Knights also set about to convert Greek Orthodox Russia to Roman Catholicism but were badly defeated by Prince Alexander Nevsky of Novgorod in the the Battle on Lake Peipus in 1242. A stunning, dramatic, fictional recreation of this battle may be seen in the 1938 film. 'Alexander Nevsky' made by Sergei Eisenstein, an acknowledged cinematic genius. The complete 107 minute film is available at Google Video, without charge. This Soviet film portrays the struggle of Prince Alexander Nevsky and the citizens of Novgorod against invasion by the Teutonic Knights, culminating in an epic battle on the ice of Lake Chudskoe (Peipius). Prince Alexander Nevsky was later canonized by the Russian Orthodox Church and became a Russian national hero. This film was produced on the eve of World War II and alludes to the threat of Nazi Germany (note the swastikas on the Catholic bishop's mitre).

In 1328, King Albert of Sweden gave Gotland - a powerful international maritime, trading center - to the Teutonic Knights in exchange for subduing dangerous pirates that seriously threatened trading and commerce. Plunging into the dispute involving the Brandenbergers claim to the Duchy of Pomerania, the Teutonic Order gained control of the great city of Danzig and all of Pomerania by 1309. However, Poland's access to the Baltic sea was now cut off and the Teutonic Knights had made a strong enemy. Furthermore, the Knights Templar in France had been destroyed and the Papacy had begun legal action against the Teutonic Order. The Teutonic Order's rule now extended over Prussia, Livonia, Semigalia, and Estonia. Lithuania and Poland were about to join forces to stop the expansionary plans of the Teutonic Knights which had continued after Lithuania had converted to Christianity.

In 1252, the Teutonic Knights captured the Lithuanian city of Klaipeda from local Baltic tribes, and cut off Lithuania's access to the Baltic Sea. In 1253, King Mindaugas sued for peace and accepted Christianity but the wars with the Teutonic Order continued. Lithuanian Grand Duke Gediminas came to power in 1316 and enlarged Lithuania south and into Russia. In 1337 Emperor Louis IV allegedly granted the Order an imperial privilege to conquer all of Lithuania and Russia. The Baltic states were now the last significant region in Europe that had not yet converted to Christianity, in which the 'old religion' still thrived. Knights from western European countries who had returned from the eastern Crusades, joined the Teutonic Knights. Fighting was fierce and the Lithuanians were enslaved en masse. The northern Estonians rebelled against the Danes in 1343-4, were subdued but the Danes withdrew and sold their lands to the Livonian Order.

In 1386, the Grand Duke of Lithuania was baptised and then married the Queen of Poland. A powerfull alliance was forged that would take on the Teutonic Knights in subesquent years. "The Lizard Union was created in 1397 by Polish nobles in Culmerland to oppose the Order's policy. In 1407 the Teutonic Order had reached its greatest territorial extent and included the lands of Prussia, Pomerelia, Samogitia, Courland, Livonia, Estonia, Gotland, Dagö, Ösel, and the Neumark pawned by Brandenburg in 1402."

The almost total negation of the military prowess of the Teutonic Order occurred at the Battle of Grunwald, 15 July 1410. A combined Polish–Lithuanian army, led by Vytautas, Grand Duke of Lithuania and King Ladislaus of Poland brought together a diverse coalition that included Muslim Tatars, and Hussite Bohemians. Grand Master Ulrich von Jungingen and most of the Order's leadership was killed in this battle, although a field army of about 10,000 survived. Granted the First Peace of Thorn in 1411 allowed the Teutonic Order to retain its lands but the mystical belief that the Teutonic knights were invincible in battle had been broken. The headquarters of the order moved again, this time to Königsberg (1466–1525).