Following the worst oil spill in US history, Macondo crude oil from the Deepwater Horizon spill and Corexit 9500 dispersant were applied in experimental dosing of the common reef sponge, Cinachyrella alloclada, found in both the GOM and many Caribbean reefs. Physiological monitoring included baseline descriptions of a) tissue ultrastructure by electron microscopy, b) profiling the sponge microbiome and c) preliminary RNA−sequencing of the host transcriptome. SEM revealed novel (embryo−like) structures. Under closed aquaculture conditions, C. alloclada individuals (n > 75) were dosed with sublethal amounts of oil or 10:1 oil/Corexit mixtures for 1, 24 and 48 hours. Unexpectedly, microbial communities of the same sponge host diverge into two distinct 16S rRNA clades after PCA analysis. Additionally, over 8000 sponge transcriptome sequences were identified; with oil and/or Corexit dosed samples having increased expression of protein transport and breakdown, cytochrome P450, and DNA repair responses. Predicted metabolite turnover demonstrated differential metabolism of sulfur−containing and phenolic compounds.