Background: This study prospectively assessed the combined versus individual effects of reducing energy intake (EI) and increasing physical activity (PA) on body weight and composition in older adults with overweight/obesity and metabolic syndrome. The interaction between both exposures was likewise assessed. Methods: A subsample of 1,110 participants (aged 55-75 years) from the Prevención con Dieta Mediterránea-Plus (PREDIMED-Plus) trial was followed for 1 year. The combined effects of 1-year changes in EI and PA on reduction of ≥5% in baseline body weight and total fat, and on ≥5% increments in lean mass were examined using dual-energy X-ray absorptiometry. Multivariate logistic regression models were used to assess the combined association. Multiplicative and additive interactions were tested. Results: Participants who had reduced EI and increased PA over 1 year were significantly more likely to exhibit ≥5% reduction in body weight (odds ratio [OR], 3.24; 95% confidence interval [CI], 1.83 to 5.72) and fat mass (OR, 2.13; 95% CI, 1.23 to 3.69) and ≥5% increase in lean mass (OR, 2.46; 95% CI, 1.24 to 4.87) compared to those who had increased EI and reduced PA. A potential for biological, rather than statistical, interaction between PA and EI was found, with synergy index (>1): 1.08 (95% CI, 0.58 to 1.99) for beneficial changes in body weight, 1.88 (95% CI, 0.41 to 8.65) for fat mass, and 1.44 (95% CI, 0.43 to 4.88) for lean mass. Conclusion: Encouraging an increase in PA with complementary nutritional education to reduce dietary EI may be more effective in managing body composition in older adults with overweight/obesity and metabolic syndrome than focusing on lifestyle behaviors alone.