$$\rightleftharpoonup{xx}$$
$$\longleftharp{xx}$$,
$$\longrightharp{xx}$$,
Terminal handling procedures in operating rooms are critical for patient safety and infection prevention, yet the relationship between nurses’ self-efficacy and terminal handling outcomes remains underexplored. This prospective observational cohort study, reported according to the STROBE framework, examined associations between perioperative nurses’ self-efficacy and terminal handling outcomes, and explored team collaboration and perceived stress as mediators. The study was conducted from January 2023 to December 2024 at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, with an analytical sample of 207 perioperative nurses. Self-efficacy was modeled as a continuous Nursing Professional Self-Efficacy Scale Version 2 (NPSES-2) score; median-split high and low groups were retained only for descriptive presentation. Primary outcomes were procedural completion time, protocol accuracy, safety compliance rate, documentation completeness, and equipment readiness time. Secondary outcomes were surgical site infection rates, patient satisfaction, nurse stress, and team collaboration. Higher self-efficacy was associated with shorter procedural completion time (18.3 ± 4.7 vs 26.8 ± 7.2 min, p < 0.001), higher protocol accuracy (94.2 ± 6.8 vs 86.4 ± 9.3, p < 0.001), and higher safety compliance (96.7 ± 3.4% vs 89.2 ± 6.1%, p < 0.001). It was also associated with lower surgical site infection rates (3.2% vs 8.1%, OR = 0.37, 95% CI: 0.22 to 0.63, p < 0.001) and higher patient satisfaction (8.7 ± 1.2 vs 7.2 ± 1.8, p < 0.001), with interpretation limited by observational case assignment and team-based perioperative care. In continuous multivariable models, the NPSES-2 score was independently associated with procedural completion time and safety compliance after adjustment for nurse, assignment, and case-context covariates, with team collaboration and stress reduction partially mediating this association. Findings support targeted professional-development interventions, including competency-based training, mentorship, and organizational support, while emphasizing that causal effects require prospective interventional confirmation.