Background: High regenerative and proliferative capacity of blood and its components renders it to be at higher risk of adverse drug reactions (ADRs) which are manifested in several treatment regimens against various ailments such as cancers, viral diseases, and several metabolic disorders. Objective: It is prudent to come up with some therapeutic entity that can prevent this damage and protects the blood from these ADRs. Materials and Methods: We examined protective effects of Plumbago zeylanica (PZ) and its active constituent plumbagin (PL) on Sprague Dawley (SD) rats using a phenylhydrazine (Phz) induced hematotoxicity model. Hemoglobin (Hgb), red blood cells (RBCs), mean corpuscular volume, mean corpuscular Hgb (MCH), MCH concentration (MCHC), leukocytes and platelets were studied. Anti-oxidant enzymes superoxide dismutases 2 and 3 (SODs) and nuclear erythroid 2 p45-related factor 1 and 2 (Nfer-1 and 2) were also studied using quantitative real-time polymerase chain reaction (PCR). Results: In Phz treated rats, the positive hematotoxic response was obtained in terms of deviated endpoints of blood indices. In PLtreated groups protective response was obtained in terms of normal endpoints of blood indices. In PCR studies, we observed the similar trend. Thus, it can be postulated that PL exerts its protective effects via modulation of anti-oxidant enzymes. Conclusion: The study proves that PL can be employed against combatting the ADRs associated with several therapeutic treatment regimens. Similar studies employing such pharmacological entities and their combinations may further prove to be effective against ADRs, especially in the context of blood cells.