Work on Santa Maria delle Grazie began in 1463. Guiniforte Solari was the main architect and designed the convent and the Gothic nave, which was complete by 1469. Ludovico Sforza decided the church would serve as the Sforza family burial site, and he rebuilt the cloister and apse, completed after 1490. The apse design is attributed to Donato Bramante, because his name is inscribed on marble in the vaults, but some scholars dispute that he worked here. One source dates his work on the crossing, dome and transept apses to 1492 to 1497.
Leonardo da Vinci's mural The Last Supper is in the refectory.
On the night of August 15, 1943, an Allied raid hit the church and convent. Much of the refectory was destroyed, but the wall bearing The Last Supper survived, having been sandbagged beforehand. Restoration ran from 1978 to 1999, and UNESCO listed the site in 1980.

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