Background: Secondary metabolites derived from plants have been identified as potential natural antioxidants, exhibiting robust capabilities in neutralizing oxidative stress that can emerge under various pathological conditions. Aim: The aim of this study was to analyze the phytochemical composition of ethanolic extract of Drynaria coronans (D. coronans), and its antioxidant potential along with α-amylase inhibition and oral toxicity studies. Methods: Preliminary qualitative phytochemical screening was conducted for D. coronans while quantitative phytochemical analysis involved the estimation of total phenolic and flavonoid contents. In vitro antioxidant activities were evaluated by using ferrous reducing-antioxidant power (FRAP), hydrogen peroxide (H₂O₂) scavenging activity, nitric oxide scavenging activity and DPPH free radical scavenging assays. The in vitro antidiabetic activity was evaluated by using the α-amylase inhibition assay. In vivo oral acute toxicity studies were evaluated in the rats as per the Organization for Economic Cooperation and Development guidelines. Results: The extraction yield of Drynaria coronans was found to be 11.94% using ethanol as the primary solvent and plant sample with solvent in a 4:1 ratio. Phytochemical analysis of the rhizome revealed the presence of secondary metabolites, including alkaloids, phenols, tannins, glycosides, and carbohydrates, which were further validated by TLC profiling. The dried extract contained 56.38 ± 0.09 mg gallic acid equivalent (GAE/g) of total phenols and 202.54 ± 0.22 mg quercetin equivalents (QE/g) of flavonoids. The extract demonstrated notable antioxidant properties, with IC₅₀ values of 43.59 (DPPH), 758.94 (NO), and 715.60 (H₂O₂), while also exhibiting strong reducing power (0.164 ± 0.011) at 700 nm. Additionally, it showed effective α-amylase inhibition with an IC₅₀ of 889.84 μg/mL. When tested for acute oral toxicity at a dose of 5000 mg/kg, no behavioral changes, morbidity, or mortality were observed in Swiss albino rats. Conclusion: The ethanolic extract of Drynaria coronans rhizomes have a positive correlation of total phenolic and flavonoid contents with the antioxidant, and inhibitory potential of the α-amylase.