BACKGROUND: Health care-associated infections (HAIs) remain a significant challenge worldwide, and the use of multimodal strategies is recommended by the WHO to enhance infection prevention. OBJECTIVES: To update the systematic review on facility level infection prevention and control interventions on the WHO core component of using multimodal strategies. METHODS: Data sources: Medline (by PubMed), EMBASE, CINAHL, and the Cochrane library. STUDY ELIGIBILITY CRITERIA: Randomized controlled studies, interrupted time series, and before-after studies in acute care settings, from November 24, 2015 to June 30, 2023. PARTICIPANTS: Both paediatric and adult populations. INTERVENTIONS: Infection prevention and control interventions implemented with at least three WHO multimodality elements. Assessment of risk of bias: Effective practice and organisation of care and integrated quality criteria for review of multiple study designs tools. Methods of data synthesis: Descriptive data synthesis. RESULTS: Of 5678 identified titles and abstracts, 32 publications were eligible for data extraction and analysis. Five non-controlled before-after studies were excluded due to an insufficient integrated quality criteria for review of multiple study designs score. Of the remaining 27 studies, nine reported on the effect of multimodal strategies to reduce device-associated HAIs, four on surgical site infections, eight on infections due to antimicrobial resistance and six on hand hygiene (HH) compliance. Eleven were controlled studies (randomized controlled studies or controlled before-after studies), nine interrupted time series and seven non-controlled before-after studies. Twenty-two of the studies originated from high-income countries, and the overall quality was medium to low. Twenty studies showed either significant HAI reductions or HH improvement. CONCLUSION: Most studies demonstrate a significant effect on HAI prevention and HH improvement after applying a multimodal strategy. However, the quality of evidence remains low to moderate, with few studies from low-income or middle-income countries. Future research should focus on higher quality studies in resource limited settings.