Background: Caesalpinia crista is a medicinal herb used to cure various ailments in subtropical and tropical regions of Southeast Asia. Objective: The objective of this evaluation of C. crista against free radical induced DNA and erythrocyte damage. Materials and Methods: The profiles of polyphenol and flavonoid were quantified through reversed-phase high-performance liquid chromatography. Free radical induced DNA and membrane damage were performed using H2O2as oxidative agent. Results: The total polyphenol content of C. crista leaf ethyl acetate extract (CcEA) was 94.5 ± 3.8 mg/gGAE, CcME (C. crista leaf methanol extract) was 52.7 ± 2.8 mg/gGAE, and CcWE (C. crista leaf Water extract) was 31.84 ± 1.8 mg/gGAE. Total flavonoid content of CcEA was 60.46 ± 2.3 mg/gQE, CcME was 46.26 ± 1.8 mg/gQE, and CcWE was 20.47 ± 1.1 mg/gQE. The extracts also exhibited good antioxidant activity as confirmed by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid), hydroxyl scavenging, reducing power, and total antioxidant assays. Among the three extracts, CcEA and CcME showed better protection against red blood cell (RBC) hemolysis and DNA damage as confirmed by electrophoretic study. Further, Scanning electron micrograph data showed that CcEA revealed the free radical induced structural alterations in RBC. Conclusion: These findings suggest that C. crista contains bioactive molecules and can inhibit oxidative stress and can be source of further study to use this in herbal medicine.