The facade of the church was originally in Via Piscinella. When the Madonna della Luce was built next door to it in 1513, it seemed to be appropriate to build a new facade in the original right wall of San Luca, so that the two facades would be aligned. Traces of the original facade can be seen on what is now the left side of the church. The present church was built at this time, after which its predecessor served as a crypt. The design of the facade (or sometimes just the upper part of it) is attributed to Bino Sozi. The inscription above the present portal records that the Knights of Malta rebuilt the church in 1586, in the reign of Pope Sixtus V.