Sponges (Phylum Porifera) have shown to be bio-accumulators of heavy metals, and bio-monitors for polychlorobiphenyl (PCB) contaminants. Furthermore, marine sponges fulfill many ecological functions on reef ecosystems. However, very little is known about sponge behavior in the face of environmental changes. Consequently, we report a study to develop the Caribbean reef sponge Cinachyrella spp. as a viable experimental model organism. Stemming from the Deepwater Horizon oil spill in 2010, we designed an experiment to expose 24 individual sponges to sublethal amounts (0.5 ppm) of oil (WAF), oil mixed with 10% COREXIT 9500 dispersant (CE-WAF), and dispersant only. Light and electron microscopy observations showed evidence of physical changes and the presence of oil droplets trapped in sponge mesohyl. RNA-Seq determined the corresponding differential gene expression (DGE) response of the same samples of Cinachyrella. Overall, 31,571 total sponge transcripts were eligible for genetic profiling by RSEM and DESeq2 after annotating based on the Amphimedon queenslandica genome. Also, 12,913 transcripts displayed significant DGE. Differentially expressed transcripts included heat shock proteins, cell integrity proteins, cancer related proteins, and apoptosis related protein among others. Major genetic responses to oil started after 1 hour of exposure and higher DGE response was seen after 24 hours of exposure for dispersant and oil:dispersant mixtures. CE-WAF Oil:dispersant mixtures appeared most harmful to the sponge after longer exposure This study confirmed Cinachyrella as a suitable research model organism from Florida reefs.