Background: Immuno-inflammatory, oxido-nitrosative stress, brain-derived neurotrophic factor-tropomyosin receptor kinase (BDNF-TrkB), and monoaminergic pathways involve in the pathophysiology of depression. Erigeron linifolius (EL) possesses antioxidant, anticonvulsant, antitumor, and hypoglycemic activities. Objective: To investigate the effect of EL hydroalcoholic extract (ELHA) against lipopolysachharide (LPS)-induced depressive-like behavior and neurochemical alterations in mice. Materials and Methods: Mice were pretreated with vehicle, imipramine (10 mg/kg, intraperitoneally [i. p.]), and ELHA (100 and 200 mg/kg, per oral) for 14 days, and depressive-like behavior was induced by LPS (0.83 mg/kg, i. p.). Depressive-like behavior in mice was evaluated by open-field test, forced swimming test (FST), and tail suspension test (TST). Cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-1β [IL-1β], IL-6, and IL-10), BDNF, monoamines (noradrenaline [NA], dopamine, 5-hydroxy), and oxido-nitrosative stress parameters (lipid peroxidation [LPO], glutathione [GSH], GSH peroxidase [GPx], catalase [CAT], superoxide dismutase [SOD], nitric oxide) were measured in the hippocampus (HC). Hippocampal caspase-3, nuclear factor-kappa B phosphor 65 (NF-κB p65), nuclear-related factor 2 (Nrf2), and TrkB and BDNF levels were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting. Results: Liquid chromatography-electrospray ionization-mass spectroscopy (MS)/MS analysis revealed the presence of ambrosin, friedelin, flavone, scopoletin, and luteolin in ELHA. ELHA showed significant antidepressant-like effect by decreasing the immobility time in FST and TST in LPS-challenged mice. Moreover, ELHA significantly attenuated TNF-α, IL-1β, IL-6, and LPO levels in LPS-challenged mice, whereas LPS-induced decrease in hippocampal IL-10, BDNF, GSH, GPx, CAT, SOD, and monoamine levels was also restored significantly by ELHA. RT-PCR and immunobloting results showed that ELHA significantly attenuated the upregulation of Caspase-3, NF-κB, p65, and Nrf2 and downregulation of TrkB and BDNF levels in the HC of LPS-challenged mice. Conclusion: The findings demonstrated antidepressant-like action of ELHA which could be due to the inhibition of neuroinflammation, oxido-nitrosative stress, and upregulation of TrkB-BDNF and monoaminergic pathways in the HC.