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Previous studies have examined whether spiritual well-being is associated with cancer outcomes, but minority populations are under-represented. This study examines associations of baseline spiritual well-being and change in spiritual well-being with change in distress and quality of life, and explores potential factors associated with changes in spiritual well-being among Hispanic women undergoing chemotherapy.Participants completed measures examining spiritual well-being, distress, and quality of life prior to beginning chemotherapy and at weeks 7 and 13. Participants' acculturation and sociodemographic data were collected prior to treatment. Mixed models were used to examine the association of baseline spiritual well-being and change in spiritual well-being during treatment with change in distress and quality of life, and to explore whether sociodemographic factors, acculturation and clinical variables were associated with change in spiritual well-being.A total of 242 participants provided data. Greater baseline spiritual well-being was associated with less concurrent distress and better quality of life (p lt; 0.001), as well as with greater emotional and functional well-being over time (p values lt; 0.01). Increases in spiritual well-being were associated with improved social well-being during treatment, whereas decreases in spiritual well-being were associated with worsened social well-being (p lt; 0.01). Married participants reported greater spiritual well-being at baseline relative to non-married participants (p lt; 0.001).Greater spiritual well-being is associated with less concurrent distress and better quality of life, as well as with greater emotional, functional, and social well-being over time among Hispanic women undergoing chemotherapy. Future work could include developing culturally targeted spiritual interventions to improve survivors' well-being.