Abstract Objective In this study, we aimed to assess the synergistic effects of cognitive frailty (CF) and comorbidity on disability among older adults. Methods Out of the 1318 participants from the Malaysian Towards Useful Aging (TUA) study, only 400 were included in the five-year follow-up analysis. A comprehensive interview-based questionnaire covering socio-demographic information, health status, biochemical indices, cognitive and physical function, and psychosocial factors was administered. Binary logistic regression analysis was employed to estimate the independent and combined odd ratios (ORs). Measures such as the relative excess risk due to interaction (RERI), the attributable proportion of risk due to the interaction, and the synergy index were used to assess the interaction between CF and comorbidity. Results Participants with CF (24.1%) were more likely to report disability compared to those without CF (10.3%). Synergistic effects impacting disability were observed between CF and osteoarthritis (OA) (OR: 6.675, 95% CI: 1.057–42.158; RERI: 1.501, 95% CI: 1.400–1.570), CF and heart diseases (HD) (OR: 3.480, 95% CI: 1.378–8.786; RERI: 0.875, 95% CI: 0.831–0.919), CF and depressive symptoms (OR: 3.443, 95% CI: 1.065–11.126; RERI: 0.806, 95% CI: 0.753–0.859), and between CF and diabetes mellitus (DM) (OR: 2.904, 95% Confidence Interval (CI): 1.487–5.671; RERI: 0.607, 95% CI: 0.577–0.637). Conclusion These findings highlight the synergism between the co-existence of CF and comorbidity, including OA, HD, DM, and depressive symptoms, on disability in older adults. Screening, assessing, and managing comorbidities, especially OA, HD, DM and depressive symptoms, when managing older adults with CF are crucial for reducing the risk of or preventing the development of disability.