Background: Few studies have simultaneously examined how blood biomarkers for inflammation, metabolic, and cardiovascular function are associated with disability incidence. This study aimed to comprehensively examine these associations. Methods: We used data from adults aged 50 and older in the Health and Retirement Study (n = 9250) and the China Health and Retirement Longitudinal Study (n = 6844), with biennial follow-up over a 4-year period. We defined abnormal biomarker values using standard clinical cut-off points for three biological systems. Disability burden was quantified as the cumulative number of impairments in basic and instrumental activities of daily living. Multivariate linear mixed-effects models were used to analyze the associations. Results: At baseline, 42% of participants had abnormal biomarker values in at least one system, 28% in two systems, and 7% in all three. A dose–response relationship was observed between the rate of disability accumulation and the number of systems with abnormal biomarker values. Compared to individuals with normal values across all systems, those with abnormalities in two systems had a significantly faster annual increase in disability burden (β = 0.06, 95% CI: 0.02–0.09), while those with abnormalities in all three systems exhibited an even steeper increase (β = 0.1, 95% CI: 0.05–0.16). Conclusions: The presence of abnormal levels in any two or all three of the systems significantly accelerated the rate of disability accumulation over a 4-year period. These findings highlight the importance of integrated biomarker monitoring for early identification of individuals at risk and inform the development of targeted preventive strategies.