ACY‑1215, also known as ricolinostat, is a leading histone deacetylase 6 inhibitor, which is currently being tested in clinical trials for hematological malignancies. Previous studies have reported that ACY‑1215 is not potent enough as a monotherapy for the treatment of colorectal cancer (CRC), which generally requires combination therapy for successful treatment. Therefore, the present study aimed to determine whether the synergistic interaction detected between ACY‑1215 and anticancer agents in hematological cancers could occur in solid tumors. The results of the present study indicated that ACY‑1215 exerted a potent synergistic anti-proliferative effect when used in combination with anticancer agents in CRC cells. The combination of ACY‑1215 and oxaliplatin was more potent than either drug alone, as indicated by an increase in apoptotic cells and their effects on the apoptotic pathway; ACY‑1215 and oxaliplatin cotreatment activated caspase‑3 and poly (ADP ribose) polymerase, increased B‑cell lymphoma (Bcl)‑2 homologous antagonist/killer expression, and decreased Bcl‑extra large protein, phosphorylated-extracellular signal-regulated kinase and phosphorylated-protein kinase B expression. In addition, combined treatment of ACY‑1215 and anticancer agents induced synergistic upregulation of programmed death‑ligand 1. These findings suggested that a therapeutic strategy that combines ACY‑1215 and oxaliplatin warrants attention for the treatment of solid tumors, including CRC.