Helichrysum sanguineum is a traditional Palestinian medicinal plant used for the treatment of various diseases. The current investigation aimed to estimate H. sanguineum four fractions chemical compositions, antioxidant, anti-lipase, and anti-α-amylase activities. Phytochemical screening, total phenols, flavonoids, and tannins of H. sanguineum acetone, aqueous, methanol, and hexane fractions were carried out using standard analytical methods. In contrast, the free radical scavenging properties of these fractions were determined using the colorimetric DPPH method and Trolox as a positive control. Moreover, the anti-lipase activity was estimated using porcine pancreatic lipase enzyme inhibitory assay and Orlistat as a positive control. Also, the α-amylase inhibitory activity was established by utilizing the α-amylase porcine pancreatic enzyme and the 3,5-dinitrosalicylic acid (DNSA) method with Acarbose as a positive control. The obtained results showed that the H. sanguineum hexane fraction has the highest phenol and flavonoid contents and revealed the best antioxidant activity. Moreover, the aqueous fraction of H. sanguineum showed potential inhibitions against α-amylase and lipase porcine pancreatic enzymes in comparison with Acarbose and Orlistat, respectively. This study endorses the use of the H. sanguineum aqueous fraction for further in vivo studies to determine its potential against diabetes mellitus, obesity, and oxidative stress diseases.