BACKGROUND: Infectious diseases, such as COVID-19, are high-risk factors for delirium. However, the implementation of nonpharmacological interventions faces major challenges during an infectious disease pandemic. AIMS: To evaluate the effect of the nurse-led Hospital Elder Life Program (NL-HELP) on delirium reduction among delirious patients with COVID-19. DESIGN: A single-blind randomized clinical trial. METHODS: This study recruited 122 delirious patients with COVID-19 from internal medicine wards at West China Hospital in China between January 30 and March 31, 2023. Participants were randomized to the NL-HELP group (n = 62) or the usual care group (n = 60). Patients in the intervention group received the NL-HELP protocol three times daily for 7 days. Patients in the control group received usual care. The primary outcome was the absence/presence of delirium during the intervention period measured by the 3-min Diagnostic Confusion Assessment Method. RESULTS: Fewer patients remained delirious in the NL-HELP group than in the control group. There were significantly more delirium-free days in the NL-HELP group than in the usual care group. There were no statistically significant differences between the two groups in terms of delirium severity, length of hospital stay, delirium at 30 days after discharge, 30-day readmission, 30-day mortality, physical function or quality of life. CONCLUSIONS: This study demonstrated that NL-HELP could reduce the presence of delirium in delirious patients. No effect was observed in terms of shortening the length of hospital stay, reducing 30-day mortality, or improving quality of life. IMPACT: NL-HELP may be effective in reducing the presence of delirium in delirious patients. Further research is needed to determine whether the NL-HELP can improve patient outcomes (e.g. mortality and quality of life) in a larger study. PATIENT OR PUBLIC CONTRIBUTION: Caregivers of delirious patients were invited to provide intervention strategies to prevent or abate delirium, including environmental management, orientation communications and identification of alert signs. TRIAL REGISTRATION: This study was prospectively registered at the Chinese Clinical Trial Registry (https://www.chictr.org.cn/) Identifier: ChiCTR2300067874.