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The aim of this study was to evaluate the hypoglycemic and antioxidant potential of green tomato (Physalis ixocarpa Brot.) calyxes' extracts. Three methods were used to obtain the extracts: maceration (M), ultrasound-assisted (US), and infusion. Regarding in vitro hypoglycemic evaluation, glucose diffusion assay and enzymatic inhibitory action of α-amylase and α-glucosidase were performed. Whereas, for in vivo assessment an oral starch tolerance test (OSTT) was tested with aqueous extracts [infusion (40 mg/kg b. wt.), maceration (M) water (98 mg/kg b. wt.), and US water (82.24 mg/kg b. wt.)] on male Wistar rats. Additionally, in vitro antioxidant activity of P. ixocarpa calyxes' was evaluated through inhibition of scavenging radical assay and lipid peroxidation. Extracts decreased the glucose diffusion in a range of 18%-56% compared with the negative control. Additionally, extracts inhibited α-amylase (above 80%) and α-glucosidase enzymes (above 90%). All groups treated with P. ixocarpa calyxes' significantly reduced the glucose levels at 120 min (infusion = 13.3%, M Water = 12.7%, and US Water = 19.4%) in comparison with the negative control, and similar levels to acarbose at 120 min (13.1%). Finally, extracts showed IC50 values in a range of 2.5-6.6 µg/µl for radical scavenging, and 118-199 µg/µl for lipid oxidation. Our results show that P. ixocarpa calyxes' extracts induce hypoglycemia and antioxidant effects in vitro and in vivo. PRACTICAL APPLICATIONS: The green tomato is usually consumed in Mexico, the United States, and Central America. This fruit grows inside a calyx, which is considered an agro-food waste. However, some regions of Latin America have a traditional medicine purpose for diabetes affections. To the best of our knowledge, there are no published data that supports its hypoglycemic action. The information provided will be useful to nutraceutical applications that allow value-added products and sustainable green tomato production.