Zehneria maysorensis (Wight & Arn.) Arn. is a Cucurbitaceae family leafy vegetable and habitual utilization of this could helps to recover human health system. This study evaluated the effect of in vitro digestion on the free radical, α-glucosidase and α-amylase inhibiting properties of Z. maysorensis leaf polysaccharides (ZMLP). The pre digested (427.00 ± 0.09 mg glucose equivalents/g of sample) and gastric digested (451.36 ± 2.82 mg glucose equivalents/g of sample) ZMLP significantly (p < 0.001) showed sugar content than pancreatic digested sample (82.51 ± 5.20 mg glucose equivalents/g of sample). The analyzed bioactivities of ZMLP were significantly (p < 0.001) higher after gastric digestion. This evidently proved that ZMLP easily digestible and made available for the intestine absorption in higher amount. The digestive ability and the bioactive potential of ZMLP suggest these functional foods can be used as antioxidant and anti-hyperglycemic agent in future.