Inflammation, a protective immune response, can contribute to maintaining homeostasis but can also cause harm when chronic or excessive. Citrullus lanatus has been suggested to possess antioxidant and anti-inflammatory activities that may aid in preventing and treating oxidative stress and inflammation. The main objective of this study was to evaluate the levels of phytochemicals, as well as the antioxidant and anti-inflammatory activities of Citrullus lanatus leaves extract. The ethyl acetate, hexane, butanol fraction and aqueous methanol extract were subjected to various standard quantitative phytochemical analysis, while the hexane fraction and aqueous methanol extract were subjected to standard in vitro anti-inflammatory assays. Spectrophotometric and gravimetric methods were used in this study. The in vitro anti-denaturation (stabilization) assay was used for detecting a wide range of antioxidant compounds. The ethyl acetate fraction had the highest flavonoid and polyphenol levels, followed by hexane, butanol, and aqueous methanol extract, respectively. Quantitative phytochemical analysis showed the levels of flavonoids, polyphenols, tannins, alkaloids and saponins present in the different fractions of C. lanatus. The human erythrocyte membrane stabilization assay showed that extracts were able to stabilize human red blood cell membrane against hypotonic-induced hemolysis in five different samples. The extract of Citrullus lanatus was found to have the highest antioxidant activity. This study has shown that the leaves of Citrullus lanatus can be used in ethnomedicine for the prevention and treatment of ailments caused by oxidative stress and inflammation-related diseases.