The objective was to determine the effectiveness of fluoroscopically guided genicular nerve radiofrequency ablation for painful knee osteoarthritis. Primary outcome measure was improvement in pain after 6 mos. Secondary outcomes included the Oxford Knee Score and Western Ontario and McMaster Universities Osteoarthritis Index. Two reviewers independently assessed publications before October 10, 2020. The Cochrane Risk of Bias Tool and Grades of Recommendation, Assessment, Development, and Evaluation system were used. One hundred ninety-nine publications were screened, and nine were included. Six-month success rates for 50% or greater pain relief after radiofrequency ablation ranged from 49% to 74%. When compared with intra-articular steroid injection, the probability of success was 4.5 times higher for radiofrequency ablation (relative risk = 4.58 [95% confidence interval = 2.61-8.04]). When radiofrequency ablation was compared with hyaluronic acid injection, the probability of treatment success was 1.8 times higher (relative risk = 1.88, 95% confidence interval = 1.38-2.57). The group mean Oxford Knee Score and Western Ontario and McMaster Universities Osteoarthritis Index scores improved in participants receiving genicular radiofrequency ablation compared with intra-articular steroid injection and hyaluronic acid injection. According to Grades of Recommendation, Assessment, Development, and Evaluation, there is moderate-quality evidence that fluoroscopically guided genicular radiofrequency ablation is effective for reducing pain associated with knee osteoarthritis at minimum of 6 mos. Further research is likely to have an important impact on the current understanding of the long-term effectiveness of this treatment.