The aim of this study was to obtain insight into the relationships between spiritual well-being, social support, psychological flexibility, and personality traits in women with breast cancer. The study was conducted on 64 women from Serbia (Mage = 58.36, SD = 11.30) who were undergoing radiation therapy. The Quality of Life Instrument – Breast Cancer Patient Version (QOL-BC) was used to assess spiritual well-being (religious and spiritual activities, changes in spiritual life after the cancer diagnosis, uncertainty about the future, positive changes in life following the illness, a sense of purpose/reason for being alive, and hope). Perceived social support was measured with the Medical Outcomes Study Social Support Survey (MOS- SSS), psychological inflexibility was evaluated with the Acceptance and Action Questionnaire (AAQ II), and personality traits were assessed with the Big Five Inventory (BFI). Demographic and clinical data were also collected. Multiple regression analysis showed that younger, less agreeable, and more conscientious patients were more likely to experience positive changes in life after the illness; greater perceived social support positively predicted a sense of purpose/reason for being alive, and younger, more open to experience patients tended to be more hopeful. Full mediation effect of perceived social support was revealed – participants who were more agreeable and open to experience, through greater perceived support, achieved a higher sense of purpose/reason for being alive. In contrast, conscientious and psychologically inflexible individuals perceived less support, which resulted in a reduced sense of purpose. Our results highlight the pivotal role of perceived social support, which could modulate and diminish negative psychological, spiritual, and existential consequences of breast cancer.