Pulsed-xenon-ultraviolet light (PX-UVL) is increasingly used as a supplemental disinfection method in healthcare settings. We undertook a systematic search of the literature through several databases and conducted a meta-analysis to evaluate the efficacy of PX-UVL in reducing healthcare-associated infections. Eleven studies were included in the systematic review and nine in the meta-analysis. Pooled analysis of seven studies with before-after data indicated a statistically significant reduction of Clostridium difficile infection (CDI) rates with the use of the PX-UVL (incidence rate ratio (IRR): 0.73, 95% CI 0.57–0.94, I2 = 72%, P = 0.01), and four studies reported a reduction of risk of methicillin-resistant Staphylococcus aureus (MRSA) infections (IRR: 0.79, 95% CI 0.64–0.98, I2 = 35%, P = 0.03). However, a further four trials found no significant reduction in vancomycin-resistant enterococci (VRE) infection rates (IRR: 0.80, 95% CI 0.63–1.01, I2 = 60%, P = 0.06). The results for CDI and MRSA proved unstable on sensitivity analysis. Meta-regression analysis did not demonstrate any influence of study duration or intervention duration on CDI rates. We conclude that the use of PX-UVL, in addition to standard disinfection protocols, may help to reduce the incidence of CDI and MRSA but not VRE infection rates. However, the quality of evidence is not high, with unstable results and wide confidence intervals, and further high-quality studies are required to supplement the current evidence.