INTRODUCTION: The aim of this study was to investigate the efficacy of creatine (CR) supplementation combined with strengthening exercises in knee osteoarthritis (OA). METHODS: A randomized, double-blind, placebo-controlled trial was performed. Postmenopausal women with knee OA were allocated to receive either CR (20 g·d(-1) for 1 wk and 5 g·d(-1) thereafter) or placebo (PL) and were enrolled in a lower limb resistance training program. They were assessed at baseline (PRE) and after 12 wk (POST). The primary outcome was the physical function as measured by the timed-stands test. Secondary outcomes included lean mass, quality of life, pain, stiffness, and muscle strength. RESULTS: Physical function was significantly improved only in the CR group (P = 0.006). In addition, a significant between-group difference was observed (CR: PRE = 15.7 ± 1.4, POST = 18.1 ± 1.8; PL: PRE = 15.0 ± 1.8, POST = 15.2 ± 1.2; P = 0.004). The CR group also presented improvements in physical function and stiffness subscales as evaluated by the Western Ontario and McMaster Universities Osteoarthritis Index (P = 0.005 and P = 0.024, respectively), whereas the PL group did not show any significant changes in these parameters (P > 0.05). In addition, only the CR group presented a significant improvement in lower limb lean mass (P = 0.04) as well as in quality of life (P = 0.01). Both CR and PL groups demonstrated significant reductions in pain (P < 0.05). Similarly, a main effect for time revealed an increase in leg-press one-repetition maximum (P = 0.005) with no significant differences between groups (P = 0.81). CONCLUSIONS: CR supplementation improves physical function, lower limb lean mass, and quality of life in postmenopausal women with knee OA undergoing strengthening exercises.