Diabetes mellitus (DM) is a group of systemic metabolic disorders with a high rate of morbidity and mortality worldwide. Due to the detrimental side effects of the current treatment, there is a great need to develop more effective antidiabetic drugs with fewer side effects. Natural products are a well-known source for the discovery of new scaffolds for drug discovery, including new antidiabetic drugs. The genus Helichrysum has been shown to produce antidiabetic natural products. In this investigation, the methanolic extract of H. cymosum and H. pandurifolium resulted in the isolation and identification of eleven known compounds viz 5,8-dihydroxy-7-methoxy-2-phenyl flavanone (1), pinostrobin (2), dihydrobaicalein (3), glabranin (4), allopatuletin (5), pinostrobin chalcone (6), helichrysetin (7), 5-hydroxy-3,7-dimethoxyflavone (8), 3,5-dihydroxy-6,7,8-trimethoxyflavone (9), 3-O-methylquercetin (10), and 3-methylethergalangin (11). The in vitro bio-evaluation of isolated compounds against alpha-glucosidase showed that 10, 5, and 11 demonstrated the highest alpha-glucosidase inhibitory activity with IC50 values of 9.24 ± 0.4, 12.94 ± 0.2, and 16.00 ± 2.4 μM respectively, followed by 7 and 3 with IC50 values of 18.16 ± 1.2 and 44.44 ± 0.2 μM respectively. However, none of these compounds showed a measurable inhibitory effect on alpha-amylase under the experimental conditions used except compound 10 which showed a poor alpha-amylase inhibitory activity with an IC50 value of 230.66 ± 15.8 μM. Additionally, strong total antioxidant capacities were demonstrated by 10, 5 and 7 in ferric-ion reducing antioxidant power assay (374.34 ± 69.7; 334.37 ± 1.7; 279.93 ± 0.8) µmol AAE/mmol. This is the first scientific report to be carried out on alpha-glucosidase inhibitory activities and antioxidant capacities of H. cymosum constituents and a first report on the isolation and identification of methoxyflavanoids from H. pandurifolium. Our findings suggest that these compounds are promising candidates to inhibit alpha-glucosidase as well as oxidative stress related to diabetes. Results from molecular docking provided insight into the observed in vitro alpha-glucosidase inhibitory activities for 5, 7, 10, and 11. It is envisaged that the isolated phytochemicals from these plants may contribute to the development of hypoglycemic lead compounds with anti-diabetic potential.