Lipid peroxidation and ROS generation are the pathogenesis of chronic fluoride toxicity, and its detrimental effects on human reproduction are noted drastically. The aim of the present study was to elucidate the defensive effects of soy protein concentrate (SPC) against sodium fluoride (NaF)-induced uterine dysfunction at biochemical and histological level. Rats were randomly distributed into four groups as control, NaF-treated (200 ppm), and SPC co-administered groups (20 mg and 40 mg/ 100 g body weight) for 16 days. SPC reversed the toxic effects of NaF. SPC significantly ameliorated the NaF-induced alterations of the antioxidant system in the uterus by decreasing lipid peroxidation products and by increasing antioxidant activities. SPC significantly counteracted the adverse effects of NaF on serum level of lactate dehydrogenase (LDH) and inflammatory markers Interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-?) and nuclear factor kappa-B (NF-?B). Our results also explored that lipid profile was meaningfully altered due to NaF and also focused a diminution of circulating homocysteine (Hcy) and altered lipid profiles along with a diminished quantity of serum B12 and B9. However, both the doses of SPC reverted back serum levels of B12, B9, and Hcy status in similar fashion along with its corrective action on lipid profile. NaF-treated group exhibited a marked degree of reduction in the weights of ovary and uterus with an alteration of normal tissue histology and significant diminution in serum estradiol (ES) levels without fluctuating uterine estradiol receptor-? (ER-?). However, SPC restored the normal tissue histoarchitecture and also increased the functional efficiency and expression of the ER-? receptor by overturning the ES levels in NaF-treated rats. Moreover, both the doses of SPC were effective against NaF-induced alterations, although 40 mg SPC/100 g body weight had better efficacy in ameliorating the NaF-induced adverse effects on the uterus and ovary.