BACKGROUND: To evaluate the efficacy of comprehensive physical and mental nursing for patients with acute cerebral infarction (ACI) undergoing intravenous thrombolytic therapy and its impact on patients' quality of life and psychological state. METHODS: A total of 200 patients with ACI, admitted to our hospital between December 2018 and December 2019, were included in the study. They were randomly assigned to either the control group or the experimental group using a random number table. The control group received routine care (basic care such as monitoring vital signs, assisting with daily activities, administering medications, and providing comfort measures), while the experimental group received comprehensive physical and mental nursing (physical care, phsycological surpport, education and conceling). Various parameters including quality of life index (QLI) scores, mental status scale in non-psychiatric settings (MSSNS) scores, self-rating anxiety scale (SAS) scores, self-rating depression scale (SDS) scores, National Institute of Health Stroke Scale (NIHSS) scores, changes in hemodynamic indicators, and incidence of adverse events during intravenous thrombolysis were compared between the two groups. RESULTS: The experimental group had higher QLI scores and lower MSSNS, SAS, SDS, and NIHSS scores compared to the control group ( CONCLUSION: Comprehensive physical and mental nursing for patients with ACI undergoing intravenous thrombolysis improves nursing efficacy, nursing satisfaction, quality of life, and patients' psychological state. These findings highlight the importance of implementing holistic nursing interventions to optimize patient outcomes in ACI management.