St. Luke's Lutheran Church opened in 1923 on Restaurant Row, an eatery-rich stretch of 46th Street in the midst of Manhattan’s theatre district. In 2006, the building opened a 178-seat Off-Broadway venue, which often hosted multiple shows in repertory. The venue was operated by Edmund Gaynes and West End Artists Company until its closure in 2020.
In 2022, the church replaced the old St. Luke's Theatre with Playhouse 46 @ St. Luke's, a new performance space in the same location. The Off-Broadway musical Islander was the first musical to play in the new theatre.
Playhouse 46 @ St. Luke's is approximately equidistant from two subway stops: 50th St. on the C and E line and 42nd St. - Port Authority on the A, C, and E line. The nearest bus stops are 8 Av./W 46 St. on the M20 and M104 lines and 9 Av./W 46 St. on the M11 line.