The school was first named Saint Vincent's School when it opened on Canal Street. It moved to Second Avenue in 1856 and changed its name to La Salle Academy in 1887.
In 2010, the school relocated to 215 East 6th Street, sharing the building with St. George Academy . Various offices are still located in the Second Avenue building.
Throughout its history, the school has been home to thousands of "Brothers' boys".
In 1966, the school purchased the Moskowitz and Lupowitz Restaurant on the corner of Second Avenue and 2nd Street. This became the school's annex that housed the Guidance Department, the Academic Support Center, the Art Department, Drama Club activities, Music Department and more classrooms. Today, the annex houses the offices of the President, Development, Recruitment & Admissions and the Christian Brothers' residential community.
It received an "exceeding national expectations" evaluation in its 2018 report in fall 2017, followed by a Certificate of Accreditation in May 2018 from the Middle States Association of Colleges and Schools on Elementary and Secondary Schools accreditation team. On assessing the school's Catholic charism, the school was blessed to have been given an exceptionally positive review ("with commendation") by the Christian Brothers of the District of Eastern North America.
Dr. Catherine Guerriero became La Salle's first female president in 2014.