Religious and spiritual (R/S) struggles, such as questioning of faith, existential and ethical concerns, and interpersonal conflicts, are associated with depressive symptoms. Neuroinflammation is critical in major depressive disorder (MDD) and is linked to stress associated with R/S problems. This study aimed to investigate whether the presence of DSM-5 R/S problems contributes to neuroinflammation. We recruited 93 MDD patients and 93 healthy controls with and without R/S problems. MRI-based restricted fraction (RF) values, an index of neuroinflammation, were measured in the hippocampus, amygdala, and neocortex. Depression and anxiety were assessed using the Hamilton Depression and Anxiety Rating Scales (HAM-D, HAM-A), while R/S problems were quantified using the Religious and Spiritual Struggles Scale (RSS-14). Results revealed elevated RF values in the amygdala and hippocampus of healthy individuals and MDD patients with R/S problems relative to those without R/S problems, with the highest values in MDD patients with R/S problems. Importantly, R/S problems and depressive symptoms were independent predictors of RF values in the amygdala and hippocampus but not in the cortex. Elevated cortical RF values were associated with MDD. These findings indicate that R/S struggles are not secondary manifestations of depression but may independently contribute to neurobiological changes.