Helminths have co-evolved with their hosts resulting in the development of specialized host immune mechanisms and parasite-specific regulatory products. Identification of new pathways that regulate helminth infection could provide a better understanding of host-helminth interaction and may identify new therapeutic targets for helminth infection. Here we identify the endocannabinoid system as a new mechanism that influences host immunity to helminths. Endocannabinoids are lipid-derived signaling molecules that control important physiologic processes such as feeding behavior and metabolism. Following murine infection with Nippostrongylus brasiliensisis (Nb), an intestinal nematode with a similar life cycle to hookworms, we observed increased levels of endocannabinoids (2-AG, AEA) and the endocannabinoid-like molecule OEA in the infected lung and intestine. To investigate endocannabinoid function in helminth infection, we employed pharmacological inhibitors of cannabinoid subtype receptor 1 and 2 (CB1R and CB2R). Compared to vehicle-treated mice, inhibition of CB1R but not CB2R resulted in increased Nb worm burden and egg output, associated with significantly decreased expression of T helper type 2 cytokine IL-5 in intestinal tissue and splenocyte cultures. Strikingly, bioinformatic analysis of genomic and RNA-seq datasets identified putative genes encoding endocannabinoid biosynthetic and degradative enzymes in many parasitic nematodes. To test the novel hypothesis that helminth parasites produce their own endocannabinoids, we measured endocannabinoid levels in Nb by mass spectrometry and quantitative PCR and found that Nb parasites produced endocannabinoids, especially at the infectious larval stage. To our knowledge, this is the first report of helminth and host-derived endocannabinoids that promote host immune responses and reduce parasite burden.