Diabetic retinopathy (DR), as the most frequent microvascular complication of diabetes mellitus (DM), causes vision loss and blindness in adults worldwide with increasing incidence. MicroRNAs (miRNAs) are involved in the regulation of DR. However, the role of miR-542-5p is still unknown. Here, we demonstrate that miR-542-5p is down-regulated in patients with DR and in high-glucose (HG)-treated retinal pigment epithelial cells. Moreover, miR-542-5p overexpression inhibits apoptosis in retinal pigment epithelial cells exposed to HG. The interaction between miR-542-5p and co-activator-associated arginine methyltransferase 1 (CARM1) is confirmed. MiR-542-5p mimics decrease the CARM1 level and miR-542-5p inhibitor increases the CARM1 level. Additionally, CARM1 overexpression promotes the miR-542-5p-mediated apoptosis in HG-treated retinal pigment epithelial cells. In summary, the data suggest that miR-542-5p may suppress apoptosis in retinal pigment epithelial cells via targeting CARM1, which provides a new therapeutic target for the treatment of patients with DR.