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Sphingolipids derived from Bacteroides species are associated with changes in host inflammation and metabolic syndrome; however, the signaling mechanisms within host cells are unknown. We utilize outer membrane vesicles (OMVs) from wild-type and sphingolipid-deficient Bacteroides strains to understand how these lipids modulate host inflammation. Characterization of the lipidome of B. thetaiotaomicron OMVs revealed enrichment of dihydroceramide phosphoethanolamine (CerPE). OMVs deliver bacterial sphingolipids into host dendritic and epithelial cells, where a subset of lipids, including CerPE, stably persist. Similarly, B. thetaiotaomicron colonization results in sphingolipid persistence in murine tissues and host lipidome alterations that are not observed with the sphingolipid-deficient strain. OMVs induce a potent, sphingolipid-dependent interleukin-10 (IL-10) anti-inflammatory response in dendritic cells, which depends on mevalonate pathway activation. Adding a CerPE fraction to sphingolipid-deficient OMVs rescued IL-10 secretion, similarly dependent on mevalonate pathway activation. These data highlight the essential roles of sphingolipids in stimulating anti-inflammatory responses mediated by mevalonate pathway induction.