Estrogen-based hormone therapy (HT) in postmenopausal women may reduce the risk of Alzheimer’s disease (AD), although HT remains controversial. One key concern with HT is the potential of adverse outcomes such as breast and uterine cancer. A promising strategy to maximize HT benefits and minimize HT risks is the use of selective estrogen receptor modulators (SERMs) that exert tissue-specific estrogenic effects. To begin investigating the SERM approach in reducing the risk of AD, we investigated whether AD-like neuropathology in the 3xTg-AD mouse model of AD is regulated by the SERMs propylpyrazole triol (PPT) and diarylpropionitrile (DPN) that exhibit relative specificity for estrogen receptor-α and -β, respectively. Consistent with our previous observations, we found that ovariectomy-induced hormone depletion in adult female 3xTg-AD mice significantly increased accumulation of β-amyloid protein (Aβ) and decreased hippocampal-dependent behavioral performance. Treatment with 17β-estradiol (E2) prevented the ovariectomized-induced worsening of both pathologies. PPT treatment was similar to E2 in terms of reducing Aβ accumulation in hippocampus, subiculum, and amygdala but comparatively less effective in frontal cortex. In contrast, DPN did not significantly reduce Aβ accumulation in hippocampus and subiculum, was partially effective in frontal cortex, and nearly as effective as E2 in amygdala. Furthermore, PPT but not DPN mimicked the ability of E2 to improve behavioral performance. These findings provide initial evidence of beneficial actions of SERMs in a mouse model of AD and support continued investigation of SERMs as an alternative to estrogen-based HT in reducing the risk of AD in postmenopausal women.