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Background: Since the beginning of 2020, the world has been grappling with a common problem, the coronavirus or COVID-19, causing a significant increase in worry, anxiety, and stress worldwide. In Iran, the rapid spread of the COVID-19 virus has posed serious threats to individuals' physical and mental health. Due to their extensive physical contact with infected individuals, medical staff experience high anxiety levels compared to other members of society. Objectives: The present study aimed to investigate the effectiveness of the acceptance and commitment approach on the resilience, self-compassion, and corona disease anxiety of medical staff involved in the COVID-19 response in Hamadan, Iran. Methods: This study utilized a semi-experimental design, including pre-test, post-test, follow-up, and control group. The study population included all medical staff involved in the COVID-19 response in Hamadan in 2021. From this population, 40 individuals were purposively selected and randomly assigned to either the experimental or control groups (20 participants in each group). Before the intervention, both groups underwent measurements (pre-test) using the Connor and Davidson Resilience Questionnaire (2003), the Neff Self-Compassion Scale (2003), and Alipouret al.'s Corona Disease Anxiety Questionnaire (2018). After the intervention of acceptance and commitment therapy for the experimental group, the same tests were conducted again for both groups (post-test). Finally, three months later, the same measurements were repeated for both groups (follow-up). The data were analyzed using repeated measures analysis of variance in SPSS-25. Results: The findings demonstrated the significant impact of acceptance and commitment therapy in enhancing resilience (P ≤ 0.001) and self-compassion (P ≤ 0.001), as well as reducing COVID-19 anxiety among the medical staff in Hamadan (P ≤ 0.001). Moreover, these effects remained stable during the follow-up phase. Conclusions: The results underscore the importance of utilizing acceptance and commitment therapy to enhance resilience and self-compassion while reducing anxiety among medical staff managing the disease. Additionally, hospital educational and executive managers should prioritize training medical staff in acceptance and commitment skills to effectively address COVID-19 anxiety. [ABSTRACT FROM AUTHOR]