Background: Doxorubicin (DOX) is a highly effective chemotherapeutic agent which use has been restricted due to its multi-organ toxicity. Objective: We investigated the possible protective effect of Calligonum comosum extract (CCE) against DOX toxicity while identifying its major phytoconstituents. Materials and Methods: CCE was administered at 100 mg/kg b.w for 2 weeks to rats which have previously received an intraperitoneal injection of DOX (20 mg/kg). Major phytoconstituents of CCE were assessed using high-performance liquid chromatography and UPLC/MS/MS. Results: CCE was rich in phenolic constituents, especially proanthocyanidins, corresponding to a concentration of 167 mg catechin per gram of the extract after hydrolysis. Other constituents identified were procyanidin B1-gallate, procyanidin B2-gallate, quercetin, and kaempferol. Animals that received CCE following DOX injection showed less signs of oxidative stress (indicated by levels of malondialdehyde, superoxide dismutase, and reduced glutathione), DNA fragmentation, and hepato-renal genotoxicity (Comet's assay). When compared to animals that received DOX only, administration of CCE following DOX maintained normal tissue architecture and restored liver and kidney functions to near their normal levels (measured as creatinine, glucose, urea serum concentration and aspartate aminotransferase, lactate dehydrogenase, and alanine transaminase activities). Interestingly, healthy animals receiving CCE showed an increase in total lymphocyte count and phagocytic activity, whereas those receiving CCE following DOX intoxication showed no signs of immunosuppression that was observed in animals receiving DOX only. Conclusion: C. comosum is a promising candidate as a supportive treatment for those receiving DOX as a chemotherapeutic agent due to its ability to ameliorate signs of DOX toxicities.