Chemo-endocrine therapy for estrogen receptor positive (ER(+)) breast cancer exhibits acquired tumor resistance. Herbal medicines provide integrative support for breast cancer patients. Present study compared the efficacy of aqueous extracts from Lycium barbarum bark (LBB) and Lycium barbarum fruit (LBF) on ER(+) MCF-7 cells. Cellular growth and 17ß-estradiol (E2) metabolism quantified the efficacy. MCF-7 cells maintained in serum depleted medium+ E2 exhibited increased anchorage-dependent and anchorage-independent growth. LBB exhibited greater potency than LBF (95% reduction in IC50). LBB produced a 6.8-fold increase, 40% decrease, and a 3.7-fold increase in 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), and estriol (E3) formation. The corresponding values for LBF were 3.9, 33, and 10.5. LBB produced a16.3-fold and a twofold increase in 2-OHE1:16α-OHE1 and E3:16α-OHE1 ratios, whereas LBF produced a sixfold and a 2.9-fold increase. The efficacy of LBB is due to increased 2-OHE1 formation, whereas that of LBF is due to accelerated conversion of 16α-OHE1 to E3. Specific growth inhibitory profiles of LBB and LBF may be due to their distinct chemical composition and their complementary actions on E2 metabolism. This study validates a mechanistic approach to identify efficacious herbal extracts for clinical ER(+) breast cancer.