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Abstract Introduction Cocaine dependence affects millions of individuals worldwide; however, there are no pharmacotherapeutic and/or diagnostic solutions. Recent evidence suggests a role for lipid signaling in the development and maintenance of addiction, highlighting the need to understand how lipid remodeling mediates neuroadaptation after cocaine exposure. Methods This study utilized shotgun lipidomics to assess cocaine‐induced lipid remodeling in rats using a novel behavioral regimen that incorporated multiple sessions of extinction training and reinstatement testing. Results Mass spectrometric imaging demonstrated widespread decreases in phospholipid (PL) abundance throughout the brain, and high‐spatial resolution matrix‐assisted laser desorption/ionization Fourier‐transform ion cyclotron resonance mass spectrometry indicated hippocampus‐specific PL alterations following cocaine exposure. We analyzed the expression of genes involved in hippocampal lipid metabolism and observed region‐specific regulation. In addition, we found that cocaine exposure differentially regulates mitochondrial biogenesis in the brain. Conclusions This work presents a comprehensive lipidomic assessment of cocaine‐induced lipid remodeling in the rat brain. Further, these findings indicate a potential interplay between CNS energetics and differential lipid regulation and suggest a role for cocaine in the maintenance of energy homeostasis.