Population aging will be one of the major social transformations in the coming decades, with a very significant impact in all countries. The consequences of this will cause an overload of social and health services. It will be necessary to prepare for an aging population. The promotion of healthy lifestyles is necessary to increase quality of life and well-being as people age. The aim of this study was to identify and synthesize interventions in middle-aged adults that promote healthy lifestyles and translate this knowledge into health gains. We performed a systematic review of the literature with research on the EBSCO Host—Research Databases platform. The methodology followed the PRISMA guidelines, and the protocol was registered with PROSPERO. A total of 10 articles out of 44 retrieved were included in this review, which identified interventions to promote healthy lifestyles with an impact on well-being, quality of life, and adherence to healthy behaviors. The synthesized evidence supports the efficacy of interventions that contributed to positive changes at the biopsychosocial level. Health promotion interventions were educational or motivational and related to physical exercise, healthy eating, and changes in habits and lifestyles related to harmful behaviors (tobacco use, excess carbohydrates in the diet, physical inactivity, and stress). The health gains found were increased mental health knowledge (self-actualization), adherence to physical exercise, improvement in physical condition, adherence to the consumption of fruits and vegetables, increased quality of life, and well-being. Health promotion interventions in middle-aged adults can significantly improve healthy lifestyles, protecting them from the negative effect of aging. For aging to be a successful experience, continuity of healthy lifestyles practiced in middle age is necessary.