We conducted an uncontrolled pilot study to determine the effects of a weight loss and walking program on knee pain and physical function in overweight and obese (body mass index; BMI [kg/m2] 25–29.9 and BMI ≥ 30, respectively) postmenopausal women with knee osteoarthritis (OA). Forty-eight such women completed self-report (Western Ontario and McMaster University Osteoarthritis Index (WOMAC)) and performance-based measures of physical function (“up & go” test, 6-min walk) and enrolled in a 6-month intervention that included weekly nutrition classes and an exercise-walking program.The intervention produced an average weight loss of 5.6 ± 4.0 kg in the 30 women who completed the program. There also were significant improvements in the 6-min walk and on VO2max. Improvements in the timed up & go test and on the WOMAC pain and function scores, however, were restricted only to women who were classified as obese at baseline. These findings suggest that a 6-month weight loss and walking program improves measures of physical functioning and pain in overweight and obese postmenopausal women with knee OA. Among obese women, functional improvement correlated with weight loss, encouraging continued emphasis on weight loss for managing knee OA.