Pulley Ridge, a limestone ridge that extends nearly 300 km along the southwestern Florida shelf in the eastern Gulf of Mexico, supports a mesophotic coral ecosystem (59 to 94 m deep), surrounded by deeper waters. An ongoing evaluation of Porifera biodiversity observed and collected during expeditions by Harbor Branch Oceanographic Institute (2003–2015) have shown the existence of approximately 102 sponge species, with at least 20 species new to science. The present paper describes two novel Poecilosclerida from mesophotic reefs and deep escarpments in the Pulley Ridge Region, Eastern Gulf of Mexico, namely Discorhabdella ruetzleri n.sp. (Crambeidae, Poecilosclerida) and Hymedesmia (Hymedesmia) vaceleti n. sp. (Hymedesmiidae, Poecilosclerida). This is the first record of Discorhabdella for the greater Caribbean and the Central West Atlantic. The skeleton of D. ruetzleri n.sp. includes the unique pseudoastrose acanthostyles of the genus, and it is distinct from congeners in the size ranges of the megascleres and in the occurrence of predominantly smooth instead of tuberose choanosomal and ectosomal subtylostyles. The intense blue color and the spicule combination of Hymesdesmia (H.) vaceleti n.sp. makes this species unique among other Hymedesmia spp. from the western Atlantic. The discovery represents a considerable expansion in the known biogeographical distribution of the genus Discorhabdella which is represented now by six species with a discrete geographic distribution (New Zealand, Azores, Western Mediterranean Sea, Eastern Pacific in Panama). This work is the first contribution to an ongoing effort to discover and document the importance of sponge biodiversity on mesophotic reefs and associated deep-water habitats in the Gulf of Mexico and the Caribbean.