Objective: This study aims to investigate the association between weight change and total knee or hip replacement (TKR or THR) for OA among middle-aged and older adults with overweight or obesity. Method: Weight data were collected in 2006–2009 and in 2010 from the 45 and Up Study—a population-based cohort aged ≥45 years in New South Wales, Australia. Participants were included if they had a baseline body mass index (BMI) ≥ 25 kg/m2 and no history of TKR or THR. Weight change was categorised into four groups: >7.5% loss; >5–7.5% loss; stable (≤5% change) and >5% gain. Hospital admission data were linked to identify TKR and THR for OA, and multivariable Cox regression was used to assess risk of TKR and THR. Results: Of 23,916 participants, 2139 lost >7.5% weight, 1655 lost 5–7.5% weight, and 4430 gained >5% weight. Over 5.2 years, 1009 (4.2%) underwent TKR and 483 (2.0%) THR. Compared to weight-stable, weight loss of >7.5% was associated with reduced risk of TKR after adjusting for age, sex, BMI, socioeconomic and lifestyle factors (hazard ratio 0.69, 95%CI 0.54–0.87), but had no association with THR. Weight loss of 5–7.5% was not associated with altered risk of either TKR or THR. Weight gain was associated with increased risk of THR after adjusting for confounders, but not TKR. Conclusion: This study suggests that a weight loss target >7.5% is required to reduce the risk of TKR in adults with overweight or obesity. Weight gain should be avoided as it increases the risk of THR.