Background: Angiopteris helferiana is used as a traditional medicine in some parts of Nepal and South-Asian countries. It is also used in traditional Chinese medicine system. Objective: In this study, we evaluated its anti-oxidant, anti-inflammatory, anti-obesity, and antidiabetic activity in cell and animal mode. Materials and Methods: The rhizome of A. helferiana was extracted with methanol and fractionated to give dichloromethane, ethyl acetate (EA), butanol (BuOH), and water fractions. The residue was again re-extracted with water to give water extract. The anti-oxidant property was measured using 1, 1-diphenyl-2-picryl-hydrazyl assay. The extract and fractions were evaluated for the α-glycosidase inhibition activity. The antiadipogenic and anti-inflammatory activity was studied in 3T3-L1–L1 and RAW 264.7 cells, respectively. The inhibition of expression of adipogenic markers peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer binding protein alpha (C/EBPα) was studied in 3T3-L1 cells. The anti-obesity and antidiabetic study was done in high-fat diet mice model. Results: The EA, BuOH fraction, and water extract showed good anti-oxidant and α-glycosidase inhibition activity. EA fraction showed good anti-inflammatory activity. EA and BuOH fraction showed good antiadipogenic activity, reducing significantly, the lipid and adipogenic markers (PPARγ, C/EBPα) in 3T3-L1 cells. The BuOH fraction at 300 mg/kg/day dose showed good anti-obesity and antidiabetic activity in the in-vivo study after the evaluation of body weight, blood lipid, blood glucose, and lipid accumulation in adipose tissue and liver. Conclusion: Overall, A. helferiana is a good source of anti-oxidative, anti-inflammatory, anti-obesity, and antidiabetic component.