Development of the Me 264 began in the late 1930s when Messerschmitt conducted work on developing a long-range reconnaissance aircraft, designated P.1061. In early 1941, six prototypes of the P.1061 were ordered and the aircraft received the formal designation of Me 264. However, the initial order for six prototypes would shortly afterwards be dropped to three.

Progress on constructing the ordered prototypes was slow at start, but development quickly picked up the pace with the start of the Amerikabomber project in spring 1942. The project called for new very long range strategic bomber designs, resulting in several designs being proposed, among them also the Me 264.

It soon became clear that despite all the advantages of the Me 264 the aircraft would not be able to demonstrate acceptable flight characteristics due to the lack of more powerful engines at that time. Apart from the Amerikabomber project, the Me 264 was also briefly considered by the Kriegsmarine as a possible replacement for the dated Fw 200 in the maritime reconnaissance role.

The first and only prototype of the Me 264 which saw completion, flew on 23 December 1942. While undergoing modifications, the Me 264 project had its further development halted, with the sole completed prototype being used as a transport machine. In 1943, the second prototype was destroyed during an allied bombing raid. The same fate also struck the first and unfinished third prototype in July 1944. After all prototypes were lost, the Me 264 project was officially cancelled in September 1944.