It was founded in April 26, 1995 with the approval by Mayor Alfredo Lim of Manila City Ordinance (MCO) No.

Its Main Campus is located at the grounds of Mehan Gardens, Ermita in front of the Bonifacio Shrine (Kartilya ng Katipunan) and beside the Central Terminal station of LRT Line 1.

The then-City College of Manila (CCM) was originally located at the 15-storey Old Philippine National Bank Building in Escolta Street, Binondo.

This ordinance was approved by Mayor Francisco “Isko Moreno” Domagoso on 27 April 2020 and it states that “the University shall be treated as an independent and institutional department of the City of Manila wherein the management of fiscal, human resources, and all other assets shall be within its control.” The Downtown Campus was later renamed to Henry Sy Sr. Campus, after the Filipino-Chinese businessman Henry Sy.

In October 2024, Mayor Honey Lacuna and Felma Carlos-Tria led the time capsule lowering and groundbreaking of UdM 's 10-storey school building in a 1,500-square-meter lot at Vitas Skate Park.