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 (PPAR γ), 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 PPAR γ and finally upregulated PPAR γ enhances the phagocytic capacity of splenic macrophages. This finding might be useful in the study of hypersplenism and other macrophage-associated diseases.