Abstract: Patients with ulcerative colitis often suffer from mental disorders such as anxiety and depression. Previous studies demonstrated that α-D-1,6-glucan (CPA) derived from Castanea mollissima Blume can ameliorate ulcerative colitis in mice. However, its potential to alleviate accompanying depressive-like behavior in colitis-affected mice remains unexplored. To investigate this, a mouse model of ulcerative colitis (UC) exhibiting depressive-like behavior was established by permitting free access to dextran sulfate sodium (DSS) solution. The depressive-like behavior in mice was evaluated using the open field test, tail suspension test, and forced swimming test. To assess the alleviating effects of CPA on depressive-like behavior in colitis mice, histopathological staining, immunohistochemistry, enzyme-linked immunosorbent assay, western blotting, and transmission electron microscopy were employed. The results revealed that CPA intervention significantly attenuated weight loss, reduced Disease Activity Index (DAI) scores, mitigated colon shortening, and diminished pathological damage in UC mice. In behavioral assessments, CPA significantly enhanced the activity of UC mice in the open field test (P<0.01) and reduced immobility time in both the tail suspension and forced swimming tests (P<0.01). Further investigations revealed that CPA repaired pathological damage in the brain tissue of UC mice, inhibited the secretion of pro-inflammatory cytokines TNF-α, IL-1β, and IFN-γ (P<0.05 or P<0.01), and promoted the expression of the anti-inflammatory cytokine IL-10. Moreover, CPA decreased the expression of the brain inflammatory corpuscle NLRP3 (P<0.05) and mitigated brain oxidative stress by increasing superoxide dismutase (SOD) activity and decreasing malondialdehyde (MDA) content (P<0.05 or P<0.01). Additionally, Iba-1 immunohistochemical staining demonstrated that CPA inhibited microglial activation (P<0.01 or P<0.001). The results of TUNEL staining and caspase-3 immunohistochemical staining indicated that CPA also suppressed brain cell apoptosis (P<0.05 or P<0.01). In summary, CPA effectively alleviated depressive-like behavior in colitis mice by inhibiting brain tissue cell apoptosis, inflammatory responses, and oxidative stress, thereby providing a theoretical basis for the prevention and treatment of colitis-related depressive symptoms using C. mollissima Blume α-D-1,6-glucan.