Hormone replacement therapy (HRT) can alleviate estrogen deficiency symptoms especially during menopause. The present study aimed at investigating the effect of soy isoflavones as HRT on immunological and bone health-related parameters with a special focus on the interactions between immunological status and metabolism. Thirty healthy cyclic female Wistar rats were used in this experiment. Ten females were sham-operated, and 20 females were subjected to ovariectomy. Overiectomized (OVX) female rats were randomly divided into 2 groups: the control group (G1, OVX/casein) was fed a casein-based diet, and the second group (G2, OVX/soy) was fed a high soy isoflavone diet. Both groups were compared to a sham-operated group (G3, sham/casein). Treatments continued for 7 weeks. Feed intake, weight gain, and lymphoid organ relative weights were recorded. Some metabolic, immunological, and bone health-related parameters were measured. Moreover, nitric oxide (NO), malondialdehyde (MDA), and total antioxidant capacity (TAC) were determined. Bone histopathology and immunohistochemistry to estrogen receptor alpha (ERα) were done. Feeding soy to OVX females reduced feed intake, weight gain, relative lymphoid organ weight, and T-lymphocytes transformation. Soy isoflavone administration normalized nearly all metabolic and immunological parameters to a level comparable to the sham group via oxidative stress amelioration and bone ERα promotion. Soy isoflavones seemed to be good HRT in estrogen deprivation which modulated the appetite, weight gain, lipid profile, proinflammation, and bone turnover.