Cancer therapy may be complicated and compromised by viral infections, including oral herpes simplex virus (HSV) infection. This network meta-analysis aimed to identify the best antiviral agent to prevent or treat oral HSV infection in patients being treated for cancer. A search was conducted for trials published since inception until the 10th of May 2020 in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. A network meta-analysis was performed on the data from randomized controlled trials that assessed antiviral agents for preventive or therapeutic activity vs. placebo, no treatment or any other active intervention in patients being treated for cancer. The agents were ranked according to their effectiveness in the prevention of oral HSV using surface under the cumulative ranking (SUCRA). Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess the certainty of the evidence. In total, 16 articles were included. The pooled relative risk (RR) to develop oral HSV infection in the acyclovir group was 0.17 (95% CI: 0.10, 0.30), compared to 0.22 (95% CI: 0.06, 0.77) in the valacyclovir group. Acyclovir ranked highest for the prevention of oral HSV followed by valacyclovir. Subgroup analysis with different acyclovir regimens revealed that the best regimens in terms of HSV-1 prevention were 750 mg/m2 acyclovir administered intravenously followed by 1600 mg per day orally. Acyclovir (250 mg/m2 per day) administered intravenously was the least effective against the prevention of oral HSV.