Sponges are recognized as a diverse and abundant component of mesophotic and deep-sea ecosystems worldwide. In Flower Garden Banks National Marine Sanctuary region within the northwestern Gulf of Mexico, sponges thrive among diverse biological and geological habitats between 16–200+ m deep (i.e., coral reefs and communities, algal nodules, and coralline algae reefs, mesophotic reefs, patch reefs, scarps, ridges, soft substrate, and rocky outcrops). A synoptic guide is presented, developed by studying common sponge species in the region, through direct sampling and in-situ photographic records. A total of 64 species is included: 60 are Demospongiae (14 orders), two are Hexactinellida (one order), and two are Homoscleromorpha (one order). Thirty-four taxa are identified to species and 13 were identified to have affinity with, but were not identical to, a known species. Fifteen taxa could only be identified to genus level, and the species remain as uncertain (incerta sedis), with the potential to represent new species or variants of known species. One specimen received only a family assignation. This study extends geographic or mesophotic occurrence data for eleven known species and includes several potentially new species. This work improves our knowledge of Gulf of Mexico sponge biodiversity and highlights the importance of the region for scientists and resource managers.