Obesity impairs humoral immunity, which is hypothesized to contribute toward chronic inflammation, poor responses to vaccination, and increased susceptibility to infections. Our research program is focused on understanding the mechanisms by which lipid metabolites synthesized from polyunsaturated fatty acids regulate humoral immunity in diet-induced obesity. Here we used a combination of metabololipidomics and immunological assays to understand how obesity impairs production of key metabolites in the context of inflammation and infection. Targeted metabololipidomic analyses across tissues revealed a reduction in the production of lipid metabolites known as specialized pro-resolving lipid mediators (SPMs) synthesized from docosahexaenoic acid. Notably, the SPM precursors 14-hydroxydoco-sahexaenoic acid (14-HDHA), 17-hydroxydocosahexaenoic acid (17-HDHA), and downstream protectin DX (PDX) were decreased in the spleens of obese male C57BL/6 J mice. Simultaneous administration of these mediators to obese male mice rescued obesity-driven decrements in the production of B cell subsets accompanied by improvements in the levels of pro-inflammatory antibodies in circulation and in adipose tissue. Administration of 14-HDHA, in particular, also improved antibody levels and the production of antibody secreting cells upon influenza A/Puerto Rico/8/34 infection. A combination of in vitro studies and experiments with 5-lipoxygenase knockouts revealed the lowering of 14-HDHA/17-HDHA/PDX was driven indirectly via B cell extrinsic mechanisms. Finally, comparative studies with female obese mice and humans revealed no impairments in the production of B cell subsets, SPMs, and pro-inflammatory antibodies. Collectively, the data suggest that metabolites of the SPM family, which are lowered in obesity in a sex-specific manner, are key regulators of humoral immunity. Therefore, targeting the abundance of these metabolites may have therapeutic value for improving inflammatory and infectious outcomes for the obese. NIH R01AT008375.