Elevated homocysteine levels and late-life depression are risk factors for cognitive decline: a comparative study highlighted the association of late-onset depression (LOD) with more significant cognitive deficits and brain pathology than early-onset depression (EOD). Limited research has explored the possible interaction between homocysteine levels and their correlation with cognitive performance in patients with EOD and LOD. Fifty-seven individuals with EOD, 56 with LOD, and 89 matched healthy controls (HC) were recruited. Global cognition, memory, execution, language, attention, visuospatial skills, and plasma homocysteine levels were examined. Compared with HC and patients with EOD, patients with LOD had higher plasma homocysteine levels ( < 0.05), with no significant difference between HC and patients with EOD ( > 0.05). Furthermore, homocysteine levels and diagnosis groups showed significant main effects on depression and cognition, with no significant interaction effects being observed. Additionally, plasma homocysteine levels were negatively correlated with global cognition, attention, visuospatial skills, and executive function in patients with LOD ( < 0.05). Compared with HC and patients with EOD, elevated homocysteine levels in patients with LOD were independently associated with cognitive performance. The potential therapeutic efficacy of homocysteine-lowering B-vitamin supplementation could be explored as a viable intervention to mitigate the documented debilitating effects of cognitive deficits in this population.