Knee osteoarthritis (OA) and frailty share pathophysiological processes and are leading causes of disability in the geriatric population; however, effective interventions remain elusive. To investigate the effects of resveratrol, on knee OA and frailty, a double-blind, placebo-controlled, randomised clinical trial was conducted over 16 weeks in patients with knee OA. 123 patients aged 63-75 years were randomised into placebo (n = 64) and resveratrol (500 mg/d; n = 59) groups. Outcome variables assessed at baseline and 16 weeks included OA evaluation using the Oxford knee score (OKS), Western Ontario and McMaster Universities (WOMAC) index, knee flexion range-of-motion (ROM), and gait speed; frailty using Fried's scale; handgrip strength (HGS); and plasma SIRT1. Resveratrol reduced frailty, pain during walking, and WOMAC scores, and improved OKS and HGS (all p < 0.05), without affecting ROM or gait speed. Patients receiving resveratrol had higher SIRT1 levels associated with frailty scores. Increased SIRT1 is linked to improved OA symptoms and reduced severity.