Photobiomodulation (PBM) therapy is an effective method for preventing and managing oral mucositis (OM) in head and neck squamous cell carcinoma (HNSCC) patients undergoing radiotherapy alone or in combination with chemotherapy. However, the potential effects of PBM therapy on premalignant and malignant cells eventually present in the treatment site are yet unknown. The aim of this systematic review was to analyze the effects of PBM therapy on HNSCC. A literature search was conducted in four indexed databases as follows: MEDLINE/PubMed, EMBASE, Web of Science, and Scopus. The databases were reviewed for papers published up to and including in October 2018. In vitro and in vivo studies that investigated the effects of PBM therapy on HNSCC were selected. From the 852 initially gathered studies, 15 met the inclusion criteria (13 in vitro and 2 in vivo). Only three in vitro studies were noted to have a low risk of bias. The included data demonstrated wide variations of study designs, PBM therapy protocols, and study outcomes. Cell proliferation and viability were the primary evaluation outcome in the in vitro studies. Of the 13 in vitro studies, seven noted a positive effect of PBM therapy on inhibiting or preventing an effect on HNSCC tumor cells, while six studies saw increased proliferation. One in vivo study reported increased oral SCC (OSCC) progression, while the other observed reduced tumor progression. Overall, the data from the studies included in the present systematic review do not support a clear conclusion about the effects of PBM therapy on HNSCC cells.