The siege of Acre (also called the fall of Acre) took place in 1291 and resulted in the Crusaders' losing control of Acre to the Mamluk Sultanate of Egypt. It is considered one of the most important battles of the period. Although the crusading movement continued for several more centuries, the capture of the city marked the end of further crusades to the Levant. When Acre fell, the Crusaders lost their last major stronghold of the Crusader Kingdom of Jerusalem.

In 1187, Saladin conquered much of the Kingdom of Jerusalem (also called the Latin Kingdom), including Acre and Jerusalem, after winning the Battle of Hattin and inflicting heavy losses on the Crusaders. The Third Crusade was launched in response; the Crusaders besieged and eventually recaptured Acre in 1191. Acre became the capital of the Kingdom of Jerusalem. The religious orders made their headquarters in and around the city, and from there made crucial military and diplomatic decisions. For example, when the Mongols arrived from the East in the mid-13th century, the Christians saw them as potential allies.

In 1250, the Mamluk Sultanate arose in Egypt; it was a more dangerous enemy than the Ayyubids. The Mamluks fielded heavy cavalry – a match for the Crusader knights – and were much more hostile. The Crusaders initially attempted to maintain a cautious neutrality with the Mamluks. In 1260, the Barons of Acre granted the Mamluks safe passage through the Latin Kingdom en route to fighting the Mongols; the Mamluks subsequently won the pivotal Battle of Ain Jalut in Galilee against the Mongols. This was an example of atypically cordial relations between the Christians and the Mamluks.

However, as early as 1261, after the Battle of Ain Jalut, Sultan Baibars led the Mamluks against the Crusaders. Baibars captured Caesarea, Haifa, and Arsuf in 1265, all the important Crusader holdings in Galilee the following year, and then Antioch in 1268.

European states launched a number of minor Crusading expeditions to reinforce the Crusader states, including the abortive Crusade of Louis IX of France to Tunis in 1270, and the minor Ninth Crusade of Prince Edward (later King Edward I) of England in 1271–1272. The expeditions failed to provide the required relief; they were too small, too short-lived, and the interests of the participants were too diverse.

More seriously, no major reinforcing Crusade was forthcoming. Pope Gregory X was unable to rally support for another great Crusade. Papal advisors blamed the lack of enthusiasm to the laziness and vice of the European nobility and to clerical corruption. A more fundamental reason seems to have been the debasement of the Crusading ideal; Gregory X's predecessors had used Crusades to raise armies against the Papacy's European enemies, such as the Albigensian Crusade declared by Innocent III against the Cathars & a crusade against the Hohenstaufen Emperor Frederick II declared by Innocent IV.

The Crusader states continued to deteriorate from continuing attacks and political instability. In 1276, the unpopular "King of Jerusalem" Hugh III moved his court to Cyprus. Under Sultan Al-Mansur Qalawun, the Mamluks captured Lattakia in 1278, and conquered the County of Tripoli in 1289. Qalawun concluded a ten-year truce with the Kingdom of Jerusalem in 1284.

Following the fall of Tripoli, King Henry II, son of Hugh III, sent seneschal Jean de Grailly to warn European monarchs of the critical situation in the Levant. Pope Nicholas IV supported Jean by writing letters urging European potentates to act. However, the Sicilian question overshadowed calls for a new Crusade, and Edward I of England was too entangled by troubles at home.