Circular RNAs (circRNAs) have critical regulatory roles in tumor biology. However, their contributions in hepatocellular carcinoma (HCC) still remain enigmatic. The present study aimed to investigate the molecular mechanisms underlying the involvement of hsa_circ_0110102 in the occurrence and development of HCC. The expression level of hsa_circ_0110102 was significantly downregulated in HCC cell lines and tissues, which was associated with poor prognosis. Knockdown hsa_circ_0110102 significantly promoted cell proliferation, migration, and invasion. Moreover, the interaction between hsa_circ_0110102 and miR-580-5p was predicted and verified by luciferase assay and RNA pull-down. The findings indicated that hsa_circ_0110102 functioned as a sponge for miR-580-5p. Moreover, miR-580-5p directly bound to the 3′ UTR of PPARα, which decreased the production and release of C-C chemokine ligand 2 (CCL2) in HCC cells. CCL2 could activate the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway in macrophage via FoxO1 in a p38 MAPK–dependent manner. Furthermore, the Δ256 mutant of FoxO1 showed no activation effect. These results concluded that hsa_circ_0110102 acted as a sponge for miR-580-5p and inhibited CCL2 secretion into tumor microenvironment by decrease the expression of PPARα in HCC cells, then inhibited the pro-inflammatory cytokine release from macrophages by regulating the COX-2/PGE2 pathway. In conclusion, hsa_circ_0110102 served as a potential prognostic predictor or therapeutic target for HCC.