San Domenico Church was built between 1441 and 1468 and represents one of the most important historical buildings of the Cosenza area (Calabria, Southern Italy) thanks to its architectonic style and the works inside, such as the “Madonna della Febbre”, a notable marble altar dated back to the XVI century. The church, as well as the sculptural group, underwent various interventions over time, unfortunately scarcely documented; thus, in this paper, the characterization of six white marble samples coming from the altar, was carried out to determine their provenance. The samples were analyzed by means of complementary methodologies well known in the archaeometric field: polarized optical microscopy (POM); an electron probe micro analyzer coupled with an energy dispersive spectrometer (EPMA-EDS); inductively coupled plasma–mass spectrometry (ICP-MS); and isotope ratio mass spectrometry (IRMS). The results provided important information about the “Madonna della Febbre” altar, suggesting the presence of different typologies of marbles and hypothesizing their possible provenance, including Carrara and Docimium. It was not clear if these marbles were re-used materials but, regardless, the reported information adds precious elements to the history of the entire architectonic complex, providing new issues to be deepened.