Melanoma is an aggressive cutaneous malignancy, but advances over the past decade have resulted in multiple new therapeutic options, including molecularly targeted therapy, immunotherapy, and oncolytic virus therapy. Talimogene laherparepvec (T-VEC) is a herpes simplex type 1 oncolytic virus, and trametinib is a MEK inhibitor approved for treatment of melanoma. Therapeutic responses with T-VEC are often limited, and BRAF/MEK inhibition is complicated by drug resistance. We observed that the combination of T-VEC and trametinib resulted in enhanced melanoma cell death in vitro. Further, combination treatment resulted in delayed tumor growth and improved survival in mouse models. Tumor regression was dependent on activated CD8 T cells and Batf3 dendritic cells. We also observed antigen spreading and induction of an inflammatory gene signature, including increased expression of PD-L1. Triple therapy with the combination of T-VEC, MEK inhibition, and anti-PD-1 antibody further augmented responses. These data support clinical development of combination oncolytic viruses, MEK inhibitors, and checkpoint blockade in patients with melanoma.