Abstract Objective Photobiomodulation (PBM) is not implemented in routine clinical management for knee osteoarthritis. This study aims to systematically investigate the effects of PBM in patients with knee osteoarthritis, comparing to placebo to understand its true clinical effects. Methods PubMed, EMBASE, Web of Science, and Cochrane databases were searched up to October 2023. Randomized placebo-controlled trials applying PBM versus placebo were included. Study characteristics, intervention parameters, and patient-reported and physical examination outcome measures were collected. The risk of bias was judged using the Cochrane risk-of-bias tool for randomized trials (version 2) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to interpret certainty of results. Results Ten studies were included comprising 542 participants. All studies were judged with unclear to high risk of bias. Meta-analysis for pain at rest (6 studies) showed that PBM significantly reduced pain at rest as compared to placebo (−0.7 [95% CI = −1.1 to −0.2]), moderate effect, very low certainty of evidence, whereas for the Timed “Up & Go” Test (3 studies), no significant effect was detected. Statistically significantly within-group (PBM) mean improvement was detected for pain, Lequesne Index, and gait performance outcomes, but not always clinically relevant or significant when compared to placebo. Conclusion PBM reduces pain intensity in patients with knee osteoarthritis and may improve disability. However, the very low certainty of evidence does not allow to recommend its isolated use but may be used to complement other widely recommended therapies. More rigorous clinical trials and the revision of the recommended dosage guidelines are warranted to increase the strength of evidence. Impact The findings indicate that photobiomodulation can reduce pain and improve disability in patients with knee osteoarthritis. However, researchers should continue to investigate isolated photobiomodulation intervention versus placebo and extend the dosage guidelines to other types of light emitters.