AbstractSpirituality is widely recognized as a potential moderator of the adverse efects of hemodialysis on mental health. Understanding its impact on mental health in Saudi Arabia and the Arab world, however, remains a signifcant research gap. Hence, this study aims to explore the correlations between spirituality, anxiety, and depression among Saudi Arabian patients undergoing hemodialysis. Using a cross-sectional design, 121 hemodialysis patients were recruited. Self-administered surveys were employed to capture demographic data, as well as a Depression and Anxiety Scale, and a Spiritual Well-being Scale. Descriptive and inferential statistics, along with multivariate regression, were utilized to analyze the data. Results show that the majority of respondents (77.7–87.6%) report moderate levels of religious well-being (RBW) and existential well-being (EWB), while 76.8–15.7% showed low-to-moderate levels of depression, respectively. Additionally, 20.7% of patients experienced moderate-to-severe anxiety. Signifcant negative correlations were found between RWB/EWB and depression (r= −0.459, r= −0.601, p<0.001, respectively) and between RWB / EWB and anxiety (r= −0.341, r= −0.536, p<0.001). The RWB accounted for 54.9% of the religious score variance, showing a strong correlation with existential score (β=0.655, p<0.001), but not with anxiety or depression. Similarly, the EWB accounted for 63.7% of the EWB variance, showing a correlation with religious score (β=0.528, p<0.001) and anxiety score (β= −0.199, p<0.05), but not with depression. In contrast, the depression explained 71.2% of the variation in depression scores, as well as showing strong correlations with anxiety (β=0.663, p<0.05). The anxiety accounted for 66.8% of the variance in anxiety scores, with depression being a signifcant predictor (β=0.763, p<0.001). This study highlights the importance of integrating spirituality into holistic care for hemodialysis patients because its presence positively infuences both mental and physical health outcomes.Keywords Cross-sectional · Saudi Arabia · Hemodialysis · Mental health · Endstage renal disease · Spiritual well-being