The study was designed to assess in vivo the effects of dried flower methanol and hexane extracts of Calendula officinalis and mitoxantrone drug on some immunological parameters (total and differential counts of leucocytes, metaphase index of bone marrow and spleen, phagocytosis, Arthus reaction, delayed type hypersensitivity reaction and plaque forming cells) and cytogenetic analyses (micronucleus formation and sperm-head abnormalities) in albino male mice. These evaluations were first made in animals treated with the assessed materials (stage I), then interactions (pre- and post-treatments) between the ideal dose of both extracts and mitroxantrone were carried out (stage II). The assessments were extended to evaluate in vitro the micronucleus formation in cell lymphocyte culture of acute myeloid leukemia (AML) patients (stage III). Chemical analyses of both extracts were also achieved. In stage I, three subcutaneous doses of both extracts (37.5, 75 and 112.5 mg/kg) and a single dose (0.33 mg/kg) of mitoxantrone were investigated, while in stage II, the first dose of both extracts was considered as an ideal one for the assessment of interactions. In stage III, three concentrations of methanol extract (92.5, 185.0 and 370.0 µg/ml) and one concentration of mitoxantrone (50.0 µg/ml) were assessed. The chemical analyses revealed that the methanol extract was positive for flavonoids, while the hexane extract was positive for steroids. Stage I results revealed that mitoxantrone showed significant immune suppressive and mutagenic actions on the biological system of treated mice. In contrast, the first dose of methanol and hexane extracts was significantly effective in enhancing the values of most immunological parameters and cytogenetic evaluations, while the effect of the next two doses was questionable in this regard. In stage II, pre- and post-treatments with the ideal dose of methanol and hexane extracts were significantly effective in modulating the immune suppressive and mutagenic effects of mitoxantrone, although the effects were subjected to the type of treatment and the parameter of evaluation. In stage III, the mitoxantrone also significantly increased the frequency of micronucleus formation in cell lymphocyte culture of AML patients and healthy controls, and the second and third concentrations of methanol extracts exerted a similar effect. In contrast, the first dose of methanol extract was effective in modulating the genotoxic effects of mitoxantrone through restoring the frequency of micronucleus formation in untreated cultures for patients and controls.