The present investigation was designed to probe into the relationship between fluctuations in gamma - aminobutyric acid (GABA) levels and depression accompanied by suicidal behavior. It aimed to explore the potential mechanistic role of GABA in the suicide risk among patients with depression and appraise its potential as a biomarker. This study employed a single - center, prospective, cross - sectional design. A total of 106 subjects were enrolled and allocated into three groups: an experimental group (patients with depression and suicidal behavior, n = 36), a control group (patients with depression but without suicidal behavior, n = 40), and a healthy control group (n = 30). Serum GABA levels were quantified, and evaluations were conducted using the Hamilton Depression Scale (HAMD), the Beck Scale for Suicide Ideation (BSS), serum cortisol levels, and brain - derived neurotrophic factor (BDNF) levels. The serum GABA level was significantly lower in the experimental group (2.50 ± 0.40 µmol/L) compared to both the control group (3.00 ± 0.30 µmol/L, p < 0.01) and the healthy control group (3.50 ± 0.20 µmol/L, p < 0.01). Conversely, serum cortisol levels were markedly elevated in the experimental group (601.18 ± 79.86 nmol/L, p < 0.01), while BDNF levels were substantially reduced (15.0 ± 3.0 ng/mL, p < 0.01). Psychological assessment scores showed that the experimental group had the highest levels of depressive symptoms and suicidal ideation, with significantly elevated HAMD and BSS scores (p < 0.001). Correlation analyses revealed that serum GABA levels were negatively correlated with BSS scores (r = -0.8444, p < 0.001), HAMD scores (r = -0.7850, p < 0.001), and cortisol levels (r = -0.6427, p < 0.001), but positively correlated with BDNF levels (r = 0.6784, p < 0.001). A significant reduction in serum GABA levels is closely associated with increased depressive severity and suicide risk. These findings suggest that GABA plays a key role in the pathophysiology of depression and suicidal behavior, potentially through modulation of the HPA axis and neuroplasticity mechanisms. Serum GABA serves as a valuable biomarker for assessing suicide risk and represents a promising target for future therapeutic interventions in depression-related suicidality.