Among 153 older Chilean adults with cognitive complaints, depression severity correlated with specific gut bacterial populations—particularly reduced Lachnospiraceae Eubacterium xylanophilum and altered Fusobacteriaceae Fusobacterium levels. Bacterial pathways metabolizing tryptophan, short-chain fatty acids, glutamate, and nitric oxide showed associations with age, sex, and cognitive performance measures. This represents the first South American evidence directly connecting gut microbiome neuroactive potential to mental health in aging populations. The findings illuminate a critical gap in our understanding of the gut-brain axis across diverse populations. While previous research established general microbiome-mood connections, this work identifies specific bacterial strains and metabolic pathways that may influence depression risk in elderly individuals already experiencing cognitive decline. The sex-specific associations suggest hormonal interactions with microbial neurotransmitter production that could explain gender differences in late-life depression rates. However, the observational design precludes causal conclusions, and the focus on cognitively impaired participants limits generalizability to healthy aging. This research advances personalized geriatric psychiatry by suggesting microbiome-targeted interventions could complement traditional depression treatments in older adults.