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Background: Reflexology is a popular non-invasive complementary medicine technique to enhance anxiety, pain, and fatigue among patients undergoing coronary angiography. Objective: This study aimed to investigate the effect of hand reflexology in ameliorating anxiety, pain, and fatigue among patients undergoing coronary angiography. Methods: A quasi-experimental research design was used on 60 patients undergoing coronary angiography at Alexandria Main University Hospital's cardiology department (30 patients in each study and control group). Four tools were used to collect data: the socio-demographic and clinical data assessment sheet, the visual analogue scale, the Rhoten fatigue scale, and the Beck anxiety inventory. Results: Scores of moderate anxiety, intractable pain, and severe fatigue among the study group significantly decreased after 2 h and three days of applying hand reflexology. Conclusion: The current study findings showed that hand reflexology is a simple, non-invasive nursing intervention that is effective and useful for managing pain, fatigue, and anxiety in patients undergoing coronary angiography as it resulted in a significant reduction in the severity of pain, fatigue, and anxiety after coronary angiography in the study group compared to the control group. Trial registration: The study was registered in the clinical trial.gov database (Clinicaltrials.gov NCT05887362, 23/05/2023). [ABSTRACT FROM AUTHOR]