The endemic threat of methicillin-resistant Staphylococcus aureus (MRSA) in nursing homes poses a serious and escalating challenge to public health administration in infection control. Nursing homes are considered as major reservoirs for MRSA colonization, with considerable high levels of colonization prevalence. We employed a computation model to evaluate effects of three intervention scenarios on MRSA colonization prevalence rate in nursing homes. Simulations were conducted using a deterministic compartmental model featuring heterogeneous contact matrix between residents and health-care workers (HCWs). Contact parameters were derived from a nursing home survey. Three intervention scenarios were simulated: (1) hand-hygiene compliance by HCWs, (2) screening-and-isolation upon admission, and (3) implementing both interventions at the same time. For every 10% reduction in average contamination duration in HCWs, the estimated average reduction in prevalence rate was 1.29 percentage point compared with the prevalence rate before the intervention was implemented. Screening-and-isolation intervention resulted in an average reduction of 19.04 percentage point in prevalence rate (S.D. = 1.58; 95% CI = 18.90–19.18). In intervention scenario 3, synergistic effects were observed when implementing hand-hygiene compliance by HCWs and screening-and-isolation together. Our results provide evidence showing that implementing multiple interventions together has a synergistic effect on colonization prevalence reduction.