Most Holy Redeemer Church was founded in 1844 by German-speaking Redemptorists to serve New York City's large German immigrant population. The current church was designed by the Munich architect, Joseph Walch, and construction was completed in October 1851. A Catholic publication of the day called Most Holy Redeemer "the most beautiful and largest (church) in New York," and it soon earned popular acclaim as "The German Cathedral of the Lower East Side.”

On November 28, 1852, Most Holy Redeemer became New York City’s first church to be consecrated. The ceremony was performed by New York’s Archbishop John Hughes and the Pontifical Mass was celebrated by Philadelphia’s bishop, a Redemptorist, the first male U.S. citizen to be canonized, Saint John Neumann.

On February 18th, 1894, Most Holy Redeemer was one of the first churches, if not the first, to have electric lighting installed.

A major overhaul of the church began in 1912. Many of the renovations are still evident. The 250-foot tower was reinforced and lowered to its current 232 feet, capped with a new copper dome and gold cross. The church’s original brick exterior was covered in some lower areas by polished granite and elsewhere with Indiana limestone. The white and black marble that runs approximately twelve feet up from the floor around the perimeter of the church was installed. Oak pews replaced the original black walnut pews and were rearranged to seat 800 people, as opposed to the original seating capacity of 1200. The sanctuary murals of the Ascension and Pentecost were retouched and two new murals, Christ on the Road to Emmaus and Peter and John Curing the Lame Man at the Temple were added. These improvements in the sanctuary were accomplished by the Rambusch Company of New York, New York. The old stained glass windows were replaced by the present ones, designed and made by the company of John Zundel, Long island, New York.

In January 1914, John Rebeschung – a parishioner, handyman, and electrical mechanic – strung wires from the sacristy of the church to the bell tower in an attempt to ring one of the bells by means of electricity. On January 11th, 1914, he proceeded to the sacristy, pressed a button, and to his excitement his experiment worked. His next task was to coordinate the bells so that they could be rung together and he was successful. Mr. Rebeschung earned the title of the inventor of this system of electric bell ringing, and Most Holy Redeemer became the first church and building in the world to have the system.

The remains of eighty-five Redemptorist priests and brothers, who ministered to the people of New York, are interred in the crypt of Most Holy Redeemer, located directly below the church.