Introduction: Healthcare-associated infections are a significant risk to patients and the healthcare system. Differences in knowledge, attitudes, and practices among nurses have limited standardized precautions. Improving self-efficacy can enhance compliance with standard precautions, protect patients, and preserve the credibility of healthcare institutions. Aim: This study aimed to determine the mediating effects of self-efficacy on nurses’ knowledge, attitude, and compliance with standard precautions in Saudi Arabia. Methods: This cross-sectional study was conducted in four hospitals in Dharan, Saudi Arabia, between July and October 2023. The respondents were selected through a multistage sampling of 305 nurses from wards and special areas. Results: participants demonstrated a moderate level of knowledge (M = 19.00, SD = 2.17), positive attitudes (M = 55.86, SD = 10.22), intermediate compliance (M = 72.44, SD = 11.47), and moderate self-efficacy (M = 29.99, SD = 11.40). Respondents who possessed more knowledge demonstrated positive attitudes toward standard precautions (r = 0.256, p < 0.001) and were more likely to comply (r = 0.376, p < 0.001). Higher self-efficacy levels were significantly positively correlated with knowledge (r = 0.391, p < 0.001), attitude (r = 0.311, p < 0.001), and compliance (r = 0.385, p < 0.001). The direct effect of knowledge on compliance was estimated to be 0.115 (p < 0.001), while the direct effect of attitude was slightly weaker (0.014, p = 0.049). Self-efficacy indirectly increased compliance through its influence on knowledge and attitude, with indirect effects of 0.039 (p < 0.001) and 0.008 (p = 0.002), respectively. Conclusions: Nurses with higher knowledge of infection control and positive attitudes toward established protocols were more likely to comply consistently. This association is further strengthened by self-efficacy. This confidence enhanced their understanding of the specific procedures, reinforced their positive beliefs about the importance of protocols, and ultimately led to greater adherence.
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