We prospectively investigate protective benefits against depression of cortical thickness across nine regions of a Ventral Frontotemporal Network (VFTN), previously associated with spiritual experience. Seventy-two participants at high and low risk for depression (Mean age 41 years; 22–63 years; 40 high risk, 32 low risk) were drawn from a three-generation, thirty-eight year study. FreeSurfer estimated cortical thickness over anatomical MRIs of the brain (Year 30) for each of the nine ROIs. Depression (MDD with SAD-L; symptoms with PHQ; Years 30 and 38) and spirituality (self-report on five phenotypes; Year 35), respectively, were associated with the weighted average of nine regions of interest. VFTN thickness was: 1) positively associated (p<0.01) with two of five spiritual phenotypes, altruism and love of neighbor, interconnectedness at a trend level, but neither commitment nor practice, 2) inversely associated with a diagnosis of MDD (SADS-L Year 30, for any MDD in the past ten years), and 3) prospectively neuroanatomically protective against depressive symptoms (PHQ-9 Year 38) for those at high familial risk.