This study was designed to determine the knowledge, compliance, and self-efficacy of standard precautions among nurses in Buraidah healthcare settings in Saudi Arabia. A cross-sectional study was conducted among 420 qualified nurses with over one year of working experience in the selected health setting. A structured self-administered questionnaire was used for data collection, including sections related to knowledge, compliance, and self-efficacy on standard precautions. Regression analysis was used to identify factors related to achieving a good level of compliance. A high rate of a good level of compliance with standard precaution (95%) was reported in this study, followed by good knowledge (73.8%) and good self-efficacy (44.8%). Factors related to education levels such as those holding a bachelor certificate or above (AOR = 6.145, 95% CI = 3.105-12.161, p = <.0001), with experiences more than 5 years, working in a less contaminated environment, being of technical title as nurses and working in public hospitals (OR = 2.885, 95% CI = 1.230-6.767, p = .015), were found highly associated with a good level of knowledge, compliance and self-efficacy of standard precaution (p<0.05). Compliance with standard precautions among the nurses was good, however, best practices for strict adherence to the standard precautions are required as the core for ensuring good healthcare quality and an adequate safe working environment. Continuous orientation and training programs are required to achieve better improvement of SP measures.