In April 2010, the Deepwater Horizon caused a large magnitude perturbation on native microbial communities across the huge range of fragile marine ecosystems located in the Gulf of Mexico. This study explored perturbations on microbial communities across a range of habitats similar to those impacted by the Deepwater Horizon spill. Our assessment utilized bioinformatics approaches taking advantage of coupled -omic datasets and publicly available information. Specifically, we developed and applied the concept of Differentially Expressed Meta pangenome to describe species-specific responses of microbial drivers to chemical exposure. This technique provided insight into contrasting strategies to respond performed by Colwellia and Marinobacter. Further inspection of microbial responses to oil-dispersant perturbations involved the application of RNA:DNA ratios (LRD score). This approach showed potential niche adaptations based on the carbon source, replication, and biosynthesis rates, especially for large carbon-degraders and methylovores. Finally, we explore the perturbations in a preconditioned microcosm allowing us to compare the variability of the microbial communities and expected functional fingerprint.