Dietary intervention in the treatment of ulcerative colitis involves, among other things, modifications in fatty acid content and/or profile. For example, replacing saturated long chain fatty acids with medium chain fatty acids (MCFAs) has been reported to ameliorate inflammation. The Black Soldier Fly Larvae’s (BSFL) oil is considered a sustainable dietary ingredient rich in the MCFA C12:0; however, its effect on inflammatory-related conditions has not been studied until now. Thus, the present study aimed to investigate the anti-inflammatory activity of BSFL oil in comparison to C12:0 using TLR4- or TLR2-activated THP-1 and J774A.1 cell lines and to assess its putative protective effect against dextran sulfate sodium (DSS)-induced acute colitis in mice. BSFL oil and C12:0 suppressed proinflammatory cytokines release in LPS-stimulated macrophages; however, only BSFL oil exerted anti-inflammatory activity in Pam3CSK4-stimulated macrophages. Transcriptome analysis provided insight into the possible role of BSFL oil in immunometabolism switch, involving mTOR signaling and an increase in PPAR target genes promoting fatty acid oxidation, exhibiting a discrepant mode of action compared to C12:0 treatment, which mainly affected cholesterol biosynthesis pathways. Additionally, we identified anti-inflammatory eicosanoids, oxylipins, and isoprenoids in the BSFL oil that may contribute to an orchestrated anti-inflammatory response. In vivo, a BSFL oil-enriched diet (20%) ameliorated the clinical signs of colitis, as indicated by improved body weight recovery, reduced colon shortening, reduced splenomegaly, and an earlier phase of secretory IgA response. These results indicate the novel beneficial use of BSFL oil as a modulator of inflammation.