OBJECTIVE: To assess the effectiveness, safety, and cost-effectiveness of genicular artery embolization (GAE) for the treatment of mild or moderate knee osteoarthritis (KO) refractory to standard treatment, and/or severe KO in individuals not eligible for surgery. METHOD: We conducted a systematic review with meta-analysis, supplemented by a cost-analysis, comparing GAE and standard treatment, from the perspective of the Spanish National Health System (NHS) over a one-year time horizon. The health improvement required for GAE to be deemed cost-effective was quantified, considering a willingness-to-pay threshold of 25 000 €/quality-adjusted life year (QALY). RESULTS: We included two randomized controlled trials in our analysis. Pain estimates showed inconsistent results, and no significant effects were observed for overall function, health-related quality of life, or changes in the need for pain management medication. No serious complications or major adverse events were observed. GRADE quality of evidence ranged from moderate to low. No economic evaluations were identified. Our cost-analysis revealed that GAE would result in an incremental cost of € 3432.37 per patient, requiring a health improvement of 0.137 QALY per patient to be deemed a cost-effective technology. CONCLUSIONS: In summary, based on moderate to low-certainty evidence, it remains inconclusive whether there is any difference between GAE and standard treatment for KO. However, the use of GAE would increase the costs. Larger randomized controlled trials are needed to determine the effects of using GAE for chronic pain secondary to KO and, consequently, to ascertain whether this technology could potentially become cost-effective from the NHS perspective.