The blue crab, Callinectes sapidus, is economically and ecologically important in western Atlantic and Gulf of Mexico estuaries. In 2010 blue crabs in the northern Gulf of Mexico were exposed to crude oil and chemical dispersants from the Deepwater Horizon oil spill. To characterize the blue crab transcriptome and identify genes that respond to oil exposure we sequenced transcriptomes from hepatopancreas and gill tissues of juvenile blue crabs exposed to a water-accommodated fraction of surrogate Macondo crude oil and compared those to transcriptomes from an unexposed control group. Illumina sequencing provided 42.5 million paired-end reads for the control group and 44.9 million paired-end reads for the treatment group. From these, 73,473 transcripts and 52,663 components (genes) were assembled. Comparison of control and treatment transcriptomes revealed about 100 genes and 2000 isoforms from each tissue type that were differentially expressed. Alternatively-spliced isoforms were identified, some showing significantly different expression patterns. Among the annotations for upregulated genes and isoforms were terms consistent with the metabolism of oil-derived compounds. Previously, few genomic resources were available for blue crabs or other brachyurans. These transcriptomes represent a major new resource for research on the biology of blue crabs, which could be used for studies of differential gene expression or as a source of genetic markers. Genes identified included candidates for responses to xenobiotic compounds, which could serve as biomarkers for oil exposure. Changes in gene expression also suggest other physiological changes that may occur as the result of exposure to oil.