Background: An adequate quality of protein intake is important for body weight management and for preventing overweight/obesity. However, beyond the source of protein, there is limited evidence on other dimensions of protein quality which may contribute to these goals. Objective: To investigate the association between the quality of dietary protein intake and long-term weight changes including the incidence of overweight/obesity. Design: We prospectively assessed middle-aged participants (37.4 ± 12.4 years) in the Seguimiento Universidad the Navarra cohort prospective cohort, using data from the 2022 dataset. Primary exposure was the multidimensional Protein source Quality Index (PQI), a previously defined metric ranging from 0 to 39.5, categorized into four levels based on cut-off points of 0.5, 1, and 2. The PQI encompasses multiple components: the types of protein-rich food sources, their essential amino acid composition, the healthfulness of these sources according to international dietary guidelines, and their impact on climate. Multivariable-adjusted associations (linear mixed models and Cox proportional hazard ratios) were examined between baseline PQI and two outcomes: long-term weight changes over an 18-year follow-up period, and the incidence of overweight and obesity. Results: Among 12,908 participants with an initial body mass index <25 kg/m2, 2,793 incident cases of overweight or obesity were identified during follow-up. Higher adherence to the PQI (category 4 [PQI >2] vs. category 1 [reference: PQI <0.5]) was associated with a reduced risk of developing overweight or obesity (HR: 0.80; 95 % CI: 0.64-0.98) compared to those with lower adherence. Furthermore, a beneficial association was observed between baseline PQI and weight loss over time, with weight differences between the extreme PQI categories of -1.37 kg (95 % CI: -1.84 to -0.89) at 14 years, -1.71 kg (95 % CI: -2.28 to -1.14) at 16 years, and -1.66 kg (95 % CI: -2.38 to -0.95) at 18 years. This indicates a significant compelling long-term impact of PQI on weight management (p for interaction <0.001). Conclusions: Our results suggest that a high PQI could be inversely associated with the incidence of overweight/obesity in a cohort of middle-aged adults and highlight the substantial role of PQI in long-term weight management. Clinical trial: NCT02669602 (https://clinicaltrials.gov/study/NCT02669602?term=SUN&locStr=Spain&country=Spain&rank=4).