Hypersplenism is a condition in which the spleen is overactive. It is common in patients with cirrhosis-related portal hypertension. The over-activated hemophagocytic splenic macrophages are an important cause of hypersplenism. MicroRNAs (miRNAs) are 21-22 nt single-stranded RNAs expressed endogenously, which play important roles in many diseases. We have found by microarray, previously, that miR-615-3p is highly expressed in splenic macrophages of hypersplenism. In this study, we found that miR-615-3p enhanced the phagocytic capacity of splenic macrophages. Bioinformatics analysis indicated that ligand-dependent nuclear receptor corepressor (LCoR) was a potential phagocytosis-related target of miR-615-3p. This was proved by dual luciferase assay and Western blot in THP-1 cells and normal/hypersplenisum splenic macrophages. Our results showed that the presence of miR-615-3p repressed the expression of LCoR, a derepressor of peroxisome proliferator-activated receptor gamma (PPARγ), which has been confirmed to be able to promote the phagocytic capacity of macrophages. In conclusion, high expression of miR-615-3p in over-activated splenic macrophages depresses LCoR expression, low level of LCoR derepresses the expression of PPARγ and finally upregulated PPARγ enhances the phagocytic capacity of splenic macrophages. This finding might be useful in the study of hypersplenism and other macrophage-associated diseases.