Reproductive dysfunction stemming from chemical agents may lead to infertility. We examined the protective effects of Calliandra portoricensis ( CP) extract on benzo[a]pyrene (BaP) and N-methyl- N-nitrosourea (NMU)-induced ovarian and uterine toxicity in rat, treated as follows: control (group 1), NMU + BaP (group 2), groups 3 and 4 received (NMU + BaP), and CP (50 and 100 mg/kg), respectively. Group 5: CP (100 mg/kg) alone, group 6: (NMU + BaP) and vincristine (VIN: 0.5 mg/kg) and group 7: VIN alone. Rats were injected at age 7, 10, and 13 weeks with single doses of NMU and BaP for 10 consecutive weeks. NMU + BaP significantly ( P < 0.05) increased ovarian and uterine weight, and decreased bodyweight, while the organo-somatic index (OSI) of uterus and ovary increased 2.3 and 1.4 folds, respectively. CP co-treatment ameliorated the observed weight changes. Lipid peroxidation increased by 58% in the ovary, accompanied by decreases in ovarian and uterine GST, GPx, catalase activities, and total sulfhydryl level in NMU + BaP-treated rats. Uterine and ovarian myeloperoxidase activities, as well as nitric oxide levels also increased. CP co-treatment ameliorated the observed changes in antioxidant enzymes and inflammatory biomarkers. Furthermore, histopathology revealed fibrotic ovarian stroma, while uterine endometrium was infiltrated with inflamed cells. Immunohistochemistry showed weak expression of FSH, LH, p53, caspase-3, and Bax, whereas progesterone, iNOS, and Bcl-2 were strongly expressed in NMU + BaP-treated rats. CP treatment restored the architecture of these tissues. Conclusively, the root bark fraction of CP decreases oxido-inflammatory damage in ovarian and uterine tissues of NMU- and BaP-treated rats. Impact statement Infertility resulting from reproductive impairment is traumatic in families. Exposure to chemicals may play insidious roles not easily connected to infertility. We examined benzo[a]pyrene (BaP), and N-methyl nitrosourea (NMU)-induced ovarian and uterine toxicity and the role of Calliandra portoricensis in mitigating toxicity. In a bid to illuminate folk medical claims cloaked in mystery, unearthing lost knowledge, advance natural chemopreventive agents, and report new evidence lacking in the literature attributed to CP. Although CP is known to exhibit anticonvulsant, antidiarrheal, antipyretic, antirheumatic, and analgesic effects in humans, its possible roles for mitigating toxicity stemming from inadvertent chemical exposures are reported here. Our findings affirm and further show that CP abates toxic response incumbent on oxidative damage and inflammatory responses associated with NMU and BaP exposure. Development of phytochemical derived from CP may serve as a potential natural therapy against chemical toxicities in individuals inadvertently exposed, and promote human health and reproductive satiety.