Advanced melanoma, a highly lethal skin cancer, causes most skin cancer–related deaths. Oncolytic monotherapy or alongside immune checkpoint inhibitors (ICIs) is emerging as a promising treatment. Evaluating the therapeutic benefit and toxicity profile of different oncolytic viruses is essential to identify the most effective option. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses–based meta-analysis was conducted to assess and contrast the therapeutic effectiveness and tolerability of herpes simplex virus (HSV) and coxsackievirus (CSV) therapies, both alone or alongside ICIs. Searches were performed in PubMed, Scopus, and clinicaltrials.gov. We extracted data on tumor objective response rates (ORRs) and the occurrence of serious (grade 3 or higher) treatment-related adverse events. Risk of bias was assessed using the ROBINS tools. Twenty trials comprising 1509 patients were included. CSV therapy demonstrated an ORR of 35%, falling between HSV monotherapy (31%) and HSV-ICI combination therapy (45%). CSV therapies, even in combination, were associated with fewer incidents of severe adverse events (17%) compared with HSV-ICI treatment (24%). HSV monotherapy also had similar fewer incidents of serious adverse events (16%). Among ICIs pembrolizumab showed the most favorable outcomes. HSV-ICI therapy showed the highest ORR but with more incidences of serious adverse events, while CSV therapy, even in combinations, offered a good safety-efficacy balance. HSV monotherapy or CSV may be favored when minimizing toxicity is a priority, even if it comes at the cost of some reduced response rate. However, combining CSV with ICIs may surpass talimogene laherparepvec monotherapy in efficacy because of the reduced likelihood of tumor resistance. Export