Objective · To investigate the safety and efficacy of focused low-intensity pulsed ultrasound (FLIPUS) therapy on the patients with knee osteoarthritis (KOA). Methods · A total of 100 subjects with KOA from August 2018 to August 2019 in the Department of Rehabilitation Medicine at the Second Affiliated Hospital of Chongqing Medical University were sequentially randomized into group A and group B. Among them, FLIPUS was adopted to treat the 50 patients in group A, and the diclofenac sodium was adopted to treat the other 50 patients in group B. Visual analogue scale (VAS), Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and Lequesne index (LI) were used to evaluate knee joint pain, the structure and function of the affected knee joint, and the severity of the affected knee joint at baseline, on day 3, day 6 and day 10 after treatment respectively. The knee range of motion (KROM) and maximum walking speed (MWS) were used to evaluate the knee joint movement and walking function at baseline and on day 10 after treatment respectively. Results · There were on significant differences between two groups with respect to KOA evaluation indexes (P>0.05). Compared with those in group B, patients in group A showed significant improvements in VAS and WOMAC scores on day 6 and day 10 after treatment (P=0.021, P=0.000; P=0.005, P=0.001). Meanwhile, patients in group A had higher LI scores than those in group B on day 10 after treatment (P=0.000). In addition, patients in group A showed significant improvements in MWS (P=0.006) and non-significant improvements in KROM (P=0.064) on day 10 after treatment. Conclusion · FLIPUS is a safe and effective treatment modality for relieving pain and improving the functions of patients with KOA.