It remains unclear whether probiotics could alleviate depression by regulating the tryptophan (Trp) metabolism and secretion of its metabolites via affecting indoleamine 2,3-dioxygenase (IDO-1). Therefore, this study was conducted to explore the underlying mechanism of Lacticaseibacillus paracasei LPB27 in resisting depression. The results demonstrated that LPB27 intervention improved the depressive-like behavior in rats with depression and reversed the altered microbiota and decreased inflammatory factors. LPB27 intervention down-regulated the expression of HMGB1, RAGE, and IDO-1, and regulated Trp metabolism in depression rats, manifested as elevated concentrations of 5-HT and 5-hydroxy-L-tryptophan (5-HTP) and decreased levels of L-kynurenine, kynurenate, picolinic acid, and cinnavalininate. Moreover, LPB27 also significantly increased the levels of dopamine (DA), norepinephrine (NE), glutamate (GLU), and gamma-aminobutyric acid (GABA). These results corroborated that LPB27 intervention could restore the disrupted homeostasis of certain gut microbiota, decrease the level of inflammation, HMGB1, RAGE and IDO-1, and regulate Trp metabolism, which collectively contributed to the improvement of depressive-like behavior.