Major depressive disorder (MDD) is a heterogeneous condition influenced by biological, psychological, and cultural factors. Recent blood-based metabolomic studies have identified alterations in pathways such as the tricarboxylic acid cycle, γ-aminobutyric acid, and the tryptophan–kynurenine axis, which are associated with depressive states, suicidality, and treatment response. In parallel, personality traits—particularly high neuroticism and low extraversion—have been shown to shape vulnerability, symptom presentation, and therapeutic outcomes. Combining personality assessment with metabolomic profiling enhances diagnostic accuracy and allows the identification of biologically distinct subtypes, separating personality-driven from personality-neutral depression. These advances hold clinical potential for improving diagnostic support, stratifying suicide risk, and tailoring individualized treatment strategies. Advancing this field will require longitudinal and multi-omics studies that incorporate digital and behavioral markers, enhanced through artificial intelligence. The aim of this review is to highlight how linking biomarkers with personality traits can foster the development of precision psychiatry, ultimately paving the way for more personalized and culturally sensitive care in depression.