Background: We report on the cost-effectiveness of photobiomodulation (PBM) for the prevention and treatment of oral mucositis (OM) derived from the cytotoxic effects of antineoplastic therapy. Methods: This review followed the PRISMA 2020 guidelines. A search was conducted in PubMed, Scopus, Web of Science, Embase, and OpenGrey. Articles published before 23 July 2024, were included. Randomized controlled trials (RCTs) that included patients with head and neck cancer undergoing chemotherapy and/or radiotherapy and a placebo group compared to an intervention group (PBM) were selected. The risk of bias was evaluated using the Joanna Briggs Institute tools. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and was rated as moderate. Results: A total of 3 RCTs and 229 patients were included. PBM may represent an additional cost in the short term, but the incremental expenses derived from the cytotoxic effects of antineoplastic therapy are greater in the medium–long term. The intervention group (PBM) showed a lower incidence of severe OM compared to the control group (placebo). Conclusions: PBM is a cost-effective long-term treatment, effective in preventing severe OM and improving the quality of life of cancer patients. More RCTs following the same standardized protocols are needed (registration CDR42024498825).