Objective: To identify the optimal exercise program, characterized by type and intensity of exercise, length of program, duration of individual supervised sessions, and number of sessions per week, for reducing pain and patient-reported disability in knee osteoarthritis (OA). Methods: A systematic review and meta-analysis of randomized controlled trials were performed. Standardized mean differences (SMDs) were combined using a random-effects model. Study-level covariates were applied in meta-regression analyses in order to reduce between-study heterogeneity. Results: Forty-eight trials were included. Similar effects in reducing pain were found for aerobic, resistance, and performance exercise (SMD 0.67, 0.62, and 0.48, respectively; P = 0.733). These single-type exercise programs were more efficacious than programs that included different exercise types (SMD 0.61 versus 0.16; P < 0.001). The effect of aerobic exercise on pain relief increased with an increased number of supervised sessions (slope 0.022 [95% confidence interval 0.002, 0.043]). More pain reduction occurred with quadriceps-specific exercise than with lower limb exercise (SMD 0.85 versus 0.39; P = 0.005) and when supervised exercise was performed at least 3 times a week (SMD 0.68 versus 0.41; P = 0.017). No impact of intensity, duration of individual sessions, or patient characteristics was found. Similar results were found for the effect on patient-reported disability. Conclusion: Optimal exercise programs for knee OA should have one aim and focus on improving aerobic capacity, quadriceps muscle strength, or lower extremity performance. For best results, the program should be supervised and carried out 3 times a week. Such programs have a similar effect regardless of patient characteristics, including radiographic severity and baseline pain.