Background <p>Population aging presents challenges for physical, mental, and social health. Serious video games have emerged as promising tools to promote active aging; however, evidence regarding their efficacy remains limited. No prior studies have integrated mood-related aspects, cognitive stimulation, and healthy lifestyle habits into a single intervention. This study aimed to assess the efficacy of a cognitive-behavioral program for promoting holistic active aging, delivered through a video game.</p> Methods <p>A total of 98 participants aged 45 and older were randomly assigned to either a cognitive-behavioral intervention group delivered through a video game (<i>n</i> = 44) or an online information control group (<i>n</i> = 54). The intervention group received eight 70-min weekly modules. The control group accessed active aging-related information via a smartphone app with a similar structure and duration. Data were collected pre- and post-intervention by blinded evaluators and through the online platform, assessing health status (general health, bodily pain, physical function, physical role, vitality, social function, emotional role, mental health, physical health factor, and mental health factor), emotional well-being, self-reported memory (satisfaction, ability, and strategies), dietary habits, physical activity, and sleep hygiene behaviors.</p> Results <p>In the intervention group, significant pre-post differences were found in general health (<i>p</i> = .006), mental health (<i>p</i> = .006), mental health factor (<i>p</i> = .047), emotional well-being (<i>p</i> = .006), satisfaction with memory function (<i>p</i> = .013), frequency of mnemonic strategy use (<i>p</i> = .046), total self-reported memory score (<i>p</i> = .042), physical activity (<i>p</i> = .003), and sleep hygiene (<i>p</i> = .030). Moreover, post-intervention analyses revealed significant improvements in general health (<i>p</i> = .005), bodily pain (<i>p</i> = .016), vitality (<i>p</i> = .002), social function (<i>p</i> = .010), physical health factor (<i>p</i> = .045), frequency of mnemonic strategy use (<i>p</i> = .035), and sleep hygiene (<i>p</i> = .004) in the intervention group compared to the control.</p> Conclusions <p>Findings support the efficacy of the cognitive-behavioral intervention delivered through an innovative interactive video game as an effective tool for fostering active and healthy aging. This approach not only demonstrates a positive impact on participants' well-being but also highlights the potential of technology in promoting health and well-being from midlife onward.</p> Trial registration <p>Code NCT03643237 (Registration date 08/05/2018, <a href="https://clinicaltrials.gov/study/NCT03643237">https://clinicaltrials.gov/study/NCT03643237</a>).</p>