ObjectiveDetermine if higher compliance with American College of Sports Medicine (ACSM) exercise prescription guidelines influences exercise outcomes in knee osteoarthritis.MethodsSystematic review. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase up to 4th January 2024 for randomised controlled trials evaluating resistance and/or aerobic exercise for knee OA. Interventions were classified as higher compliance (meeting ≥60% of ACSM guideline recommendations for frequency, intensity, duration) or lower compliance (meeting <60% of recommendations). Effects on pain and function were evaluated via meta‐analysis, stratified by compliance.Results25 trials (3,290 participants) evaluated combined resistance and aerobic programs, with no differences in outcomes between those with higher and lower compliance (standardised mean difference [SMD] pain: ‐0.38 [95% confidence interval: ‐0.59 to ‐0.17] vs ‐0.31 [‐0.45 to ‐0.16], respectively; function: ‐0.43 [‐0.64 to ‐0.21] vs ‐0.36 [‐0.58 to ‐0.14]). 66 trials (5,231 participants) evaluated resistance exercise, with no differences between interventions with higher and lower compliance (pain: ‐0.60 [‐0.81 to ‐0.39] vs ‐0.93 [‐1.27 to ‐0.59]); function: ‐0.64 [‐0.83 to ‐0.44] vs ‐0.85 [‐1.20 to ‐0.49]). 12 trials (958 participants) evaluated aerobic exercise, with no differences between interventions with higher and lower compliance (pain: ‐0.83 [‐1.27 to ‐0.38] vs ‐0.76 [‐2.02 to 0.50]; function: ‐0.79 [‐1.20 to ‐0.38] vs ‐1.00 [‐2.52 to 0.53]).ConclusionHigher or lower compliance with ACSM exercise prescription guidelines did not influence exercise outcomes. Given there was substantial heterogeneity and many publications were at risk of bias, our results should be interpreted with caution.