The Deepwater Horizon oil spill in the Gulf of Mexico is the deepest and largest offshore spill in the United State history and its impacts on marine ecosystems are largely unknown. Here, we showed that the microbial community functional composition and structure were dramatically altered in a deep-sea oil plume resulting from the spill. A variety of metabolic genes involved in both aerobic and anaerobic hydrocarbon degradation were highly enriched in the plume compared with outside the plume, indicating a great potential for intrinsic bioremediation or natural attenuation in the deep sea. Various other microbial functional genes that are relevant to carbon, nitrogen, phosphorus, sulfur and iron cycling, metal resistance and bacteriophage replication were also enriched in the plume. Together, these results suggest that the indigenous marine microbial communities could have a significant role in biodegradation of oil spills in deep-sea environments.