The original plan was the work of Giacomo della Porta though during the long construction period that stretched until 1663 several other architects were involved.

The ceiling painting of the Apotheosis of St Dominic was produced in 1674 by Domenico Maria Canuti, with trompe-l'œil framing by Enrico Haffner.

Antonio Canaletto made a pen and ink study with grey wash and black chalk, today in the collection of the British Museum, described as depicting "the Church of SS Domenico e Sisto, Rome; with a sweeping double staircase to the entrance, in the foreground a man bowing to two approaching ladies.

"[3] In 1906, American painter John Singer Sargent completed an oil painting of the exterior staircase and balustrade of the church.

[4] Sargent described the ensemble as "a magnificent curved staircase and balustrade, leading to a grand façade that would reduce a millionaire to a worm".

[5] Sargent used the architectural features from this painting later in a portrait of Charles William Eliot, President of Harvard University.