Abstract Objective To investigate whether depression mediates the relationship between right cingulum-hippocampal integrity and Logical Memory I (LM I) in Spanish-speaking Mexican Americans. Method Participants were 456 Spanish-speaking Mexican Americans (70.2% female; mean age = 63.3 years, SD = 8.05; mean education = 6.75 years, SD = 3.96) from the Health & Aging Brain Study - Health Disparities (HABS-HD). They underwent standard neuropsychological testing and MRI scans. Right cingulum-hippocampal integrity was measured using mean diffusivity. Depression was measured by the Geriatric Depression Scale (GDS). Results The total effect of right cingulum-hippocampal integrity on LM 1 performance was significant [F(1, 413} = 15.24; p < 0.001; r2 = 0.04; 95% CI = −6589.52, −2175.98]. Among the participants, 32.1% of participants reported depressive symptoms on the GDS, while only 21.1% received a clinical diagnosis. Depression demonstrated a significant indirect effect on LM 1 total score [B = −345.19; 95% CI = −811.34, −36.97]. The direct effect of right cingulum-hippocampal integrity on memory function remained significant [B = −4037.56; p < 0.001; 95% CI = −6243.45, −1831.66] even after accounting for depression. Conclusions Depression partially mediated the relationship between right cingulum-hippocampal integrity and LM 1 performance. This suggests that the effect of right cingulum-hippocampal integrity on memory encoding is modulated by depression severity. However, a significant direct effect remained even after accounting for depression, indicating independent contributions of both factors. Further research is needed to examine additional variables that may influence the relationship between right cingulum-hippocampal integrity and LM 1 performance.