Purpose: This systematic review examined the cost-effectiveness of healthcare-associated infection (HAI) prevention and control (IPC) programs across healthcare settings. Methods: A search of international and domestic databases for studies published between January 1900 and August 2025 was conducted according to PRISMA 2020 guidelines. Ten studies reporting both IPC interventions and economic outcomes were included. Data extraction included study characteristics, intervention types, cost components, and economic results. The CHEERS 2022 checklist was used for assessment of reporting quality. Results: IPC interventions included hand hygiene improvement, environmental cleaning programs, antimicrobial stewardship, screening strategies, contact precaution policies, and prophylactic therapies. Five studies reported cost-effectiveness ratios (CERs), ranging from 5.59 to 950,000, reflecting wide variation in the intensity of the intervention and cost structure. Although lacking CERs, the remaining studies consistently reported cost savings, including reductions in antimicrobial use, HAI incidence, hospital-acquired complications, and bed-day costs. Of particular importance, none of the studies reported increased post-intervention costs, indicating a positive economic impact across settings. However, reporting quality was moderate. Essential elements of economic evaluation such as perspective, time horizon, discount rate, price year, currency conversion, or uncertainty analysis were not specified in many of the studies, limiting comparability and hindering robust synthesis. Substantial heterogeneity in input definitions, outcome metrics, and cost calculation approaches also constrained quantitative pooling. Conclusion: IPC programs provide consistent economic value by reducing HAI burden and use of healthcare resources. Future studies should improve methodological rigor and adhere to CHEERS reporting standards as an effort to strengthen the evidence base. High-quality economic evaluations are particularly needed in healthcare systems where the focus of IPC research has been more on clinical outcomes than on economic impact. In addition, effective IPC implementation requires consideration of the capacity and competency of the nursing workforce, highlighting the importance of integrating nursing roles into infection control practice and policy.