Purpose: The quality of life of people with cancer can be improved by helping them discover meaning and purpose in life, even if they are faced with a potentially fatal illness. This study aimed to evaluate the reliability and applicability of the Vietnamese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Spiritual Well-being 32 (EORTC QLQ-SWB32) measurement in cancer patients. Methods: A total of 214 patients from four hospitals with cancer treatment facilities or having an oncology department were invited to participate in the study. The data were collected from November 2021 to April 2022 and analyzed for validation. Results: In this group of participants, the type of cancer with the highest prevalence rate was lung cancer (71%). The confirmatory factor analysis of construct validity with Chi-Square/df = 2.283, goodness-of-fit index = 0.846, comparative fit index = .742, and root mean square error of approximation = .078 confirmed the culturally distinguished model fit in Vietnamese people with cancer. The reliability of the instrument ranged from 0.604 to 0.749 for Relationship with Someone or Something Greater (RSG) and Relationship with Others (RO). In the group of patients who identified as having a religion, patients with no religion had lower RSG scores than Catholics or Buddhists. There were distinctions in the median Relationship with Self (RS) scores according to the severity of most Edmonton symptoms. Conclusion: The Vietnamese version of the EORTC QLQ-SWB32 tool was accepted and reliable, specifically for cancer patients in Vietnam.