Rumex dentatus L. is an annual herb commonly known as "Abuj" (Kashmir) and as toothed dock and Aegean dock (worldwide). R. dentatus L. has a strong accord of antitumor, antidermatitis, anti-inflammatory, diuretic, astringent, and bactericidal properties. To investigate the in vitro neuroprotective effects against corticosterone-induced impairment using extracts and isolated compounds from R. dentatus L., via neuronal impairment activating the BDNF-TrkB pathway. Isolation and analysis were performed by column chromatography. Spectroscopy (H NMR, C NMR, and HRMS) were applied for structural elucidation of isolated compounds. All the isolates were tested for the possible in vitro neuroprotection against corticosterone-prompted impairment, activating the BDNF-TrkB pathway, performed using electronic databases, including PubMed, Google Scholar, and Science Net, to ensure the manuscript quality. The comparative study was made with different extracts of R. dentatus L., and it was found that extracts showed remarkable antidepressant activity, which was overpowered by isolated compounds, particularly compound R3, found to be most effective. Among the panel of screened compounds, only R3 exhibited robust neurotropic activity, which increased neuronal cell survival in differentiated human neuroblastoma cells from high-dose corticosterone (400 µM) induced cell death. Small natural molecule R3 prevents corticosterone-induced neuronal impairment, activating the BDNF-TrkB pathway. In conclusion, R. dentatus L. was evaluated for the isolation of bioactive secondary metabolite composition and neuroprotection. The isolation from the root extract of chloroform and methanol fractions led to five isolates. Three natural compounds, R1, OA, and R3, were found to have promising neuroprotective potential, confirmed through in vitro testing of the isolated constituents and effects against corticosterone-induced impairment. The activation of the AKT/ERK pathway by R3 showed significant cell survival and increased neural viability in corticosterone-induced impairment in SHSY5Y cells in a concentration- and time-dependent manner. The research finding is the first of its kind where R. dentatus has been used for isolation and bio-evaluation with productive results.