Depression is one of the most common comorbidities among hemodialysis patients, with prevalence rates substantially higher than in the general population. Extensive evidence suggests that neuroticism may be a vulnerability factor for depression. However, the specific path leading from neuroticism to depression through emotion regulation strategies (such as cognitive reappraisal and expressive suppression), remains unexamined in this population. This study aims to examine whether emotion regulation strategies mediate the relationship between neuroticism and depression in Algerian hemodialysis patients. A cross-sectional study was conducted with a sample of 144 Algerian hemodialysis patients from three public hospitals. Participants completed the Big Five Inventory-44 (BFI-44), the Emotion Regulation Questionnaire (ERQ), and the Beck Depression Inventory-II (BDI-II). Data were analyzed using the PROCESS macro for SPSS with a bootstrapping technique to test the mediation model. Neuroticism demonstrated strong positive correlations with depression (r = 0.62, p < .001) and expressive suppression (r = 0.58, p < .001), and a significant negative correlation with cognitive reappraisal (r = -0.45, p < .001). The mediation analysis revealed a significant total effect of neuroticism on depression (β = 0.59, p < .001). Significant indirect effects were confirmed through both emotion regulation strategies for expressive suppression (β = 0.18, 95% CI [0.10, 0.28]) and for cognitive reappraisal (β = 0.09, 95% CI [0.04, 0.16]). The direct effect of neuroticism on depression remained significant (β = 0.32, p < .001), indicating partial mediation. These results suggested that neuroticism increased the risk of depressive symptoms in hemodialysis patients by increasing expressive suppression and decreasing cognitive reappraisal. Cognitive reappraisal seems to be a protective factor, whereas expressive suppression appears to be a vulnerable factor, with respect to mental health. These results contribute to understanding depression in hemodialysis patients, which should guide the design of tailored therapeutic interventions for this population.