BACKGROUND: Squat exercise, in which eccentric and concentric contractions are present simultaneously in different muscle groups, is one of the closed kinetic chain exercises commonly used in knee rehabilitation. OBJECTIVE: In the scope of the study, our objective is to determine the effectiveness of a structured squat-based exercise approach in patients with knee osteoarthritis. METHODS: In this study, 75 patients diagnosed with knee osteoarthritis were randomly assigned to three distinct groups: isoinertial exercise, a combination of home exercise and electrotherapy, and exercise solely. The assessment encompassed the application of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Time Up and Go test, evaluation of quadriceps and hamstring muscle strength and activation levels, along with pain threshold assessment. The treatment program was administered three days a week over a span of eight weeks and was assessed both prior to and following the intervention. RESULTS: Across all groups, considerable enhancements were noted in the majority of parameters. Particularly noteworthy were the substantial improvements observed in the first group, specifically concerning WOMAC total score (p = 0.001), muscle strength, activation levels (p = 0.001), and pain tolerance (p = 0.05). CONCLUSIONS: In the group in which we applied isoinertial exercise, a positive increase was observed in most of the parameters.We suggest that isoinertial exercise applications, which are generally encountered in sports fields, should be used in different fields in future studies.