Depression is a heterogeneous disorder and has been regarded as an inflammatory disease. The aerial parts of the Convolvulus pluricaulis are used in Indian traditional medicines for the management of nervous disorders. However, the influence of methanolic extract of aerial parts of Convolvulus pluricaulis (CPE) on a chronic animal model of depression has not been investigated yet, and associated biochemical changes are still unclear. Therefore, this study investigates the effects of CPE on a chronic rat model of depression and explores its underlying mechanism of action on neuroinflammation and brain monoamines. The antidepressant-like effect of CPE (25, 50, and 100 mg/kg, p.o.) was depicted using the sucrose preference test and the forced swimming test (FST) while CUMS-induced alteration in the locomotor index was measured using the open field test (OFT) and actophotometer. A consecutive one-week treatment of CPE (50, and 100 mg/kg) or fluoxetine (10 mg/kg, p.o.) treatment significantly increased sucrose preference index, reduced immobility time in the FST, and increased the number of squares crossed, the number of rearing in the OFT and locomotion in the actophotometer in the CUMS-exposed rats. Moreover, elevated levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and liver biomarkers ALT, AST were also significantly reversed by CPE (50, and 100 mg/kg) or fluoxetine administration in the CUMS-exposed rats. Furthermore, a one-week treatment of CPE (50 and 100 mg/kg) or fluoxetine also remarkably restored the serotonin and noradrenaline levels in the hippocampus as well as in the prefrontal cortex of the CUMS-exposed rats. However, CPE (25 mg/kg) exerted insignificant protection against CUMS-induced depressive-like behavior and associated neuroinflammation. Therefore, this study demonstrates that CPE exerted antidepressant-like effect which could be mediated by anti-inflammatory potential, restoring liver biomarkers or monoaminergic responses in the stressed rats.