Monkeypox virus (MPXV) infects diverse human cell types, and human immunodeficiency virus (HIV) co-infection is common. However, the immunometabolic consequences of MPXV infection, and how they may be altered by HIV, remain poorly defined. To address this, we performed quantitative plasma lipidomics and precise metabolomics in a discovery cohort (n = 81) comprising MPXV-monoinfected (MPLWOH), MPXV–HIV-coinfected (MPLWH), HIV-monoinfected (PLWH), and healthy controls, integrating exosome proteomics, cytokine profiling, and transcriptomics of exosome-treated HepG2 and A549 cells for functional interpretation. An independent validation cohort (n = 65) was used to assess cross-cohort reproducibility. MPXV infection induced broad lipid remodeling, with elevations in phosphatidylserine (PS) and phosphatidylethanolamine (PE), together with reductions in phosphatidylcholine (PC), lysophospholipids, cholesteryl ester (CE), and exosomal lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL). These lipid alterations were correlated with tissue injury markers and inflammatory cytokines. MPLWH patients exhibited more severe metabolic disruption, including marked sulfatide (SL) depletion, lower cholesterol and HDL-c, and extensive rewiring of lipid-cytokine associations. SL depletion in MPLWH correlated with abundances of COPI-mediated retrograde trafficking proteins in exosomes. Consistent with these systemic alterations, transcriptomic profiling of exosome-treated cells provided functional validation: MPLWOH exosomes induced lipid metabolism and repair-associated epithelial programs, while MPLWH exosomes drove phospholipid remodeling and acute inflammatory and mucosal barrier-stress responses. Collectively, MPXV infection reprograms host lipid metabolism and exosome composition, with HIV co-infection amplifying inflammatory, metabolic, and trafficking disruptions. These convergent multi-omics signatures link systemic lipid dysregulation to exosome-mediated immunomodulation and identify potential targets for host-directed interventions.