Context: Uterine Fibroid (UF) is the most common benign tumor in myometrium (MM) of reproductive age women. However, mechanism underlying disease pathogenesis is largely unknown. Objective: To explore the link between nuclear β-catenin and UF phenotype and β-catenin cross-talk with estrogen and histone deacetylases (HDACs). Design protein/RNA levels of β-catenin (CTNNB1), its responsive markers [CyclinD1, c-Myc], Androgen receptor (AR), p27 and class-I HDACs were measured in matched UF/MM tissues or cell populations. Chemical inhibition/activation and genetic knockdown (KD) of CTNNB1 were performed and their effects on UF phenotype were measured. Anti-UF Effect of two HDAC inhibitors (HDACis) was evaluated. Main Outcome Measure: β-catenin nuclear translocation in response to β-catenin inhibition/activation, estrogen and HDACis in UF cells. Results: UF tissues/cells showed significantly higher expression of nuclear β-catenin, CyclinD1, C-Myc, and HDACs (1, 2, 3, 8) than MM. Estradiol induced β-catenin nuclear-translocation and consequently its responsive genes in both MM and UF cells, while Estrogen receptor antagonist reversed this induction effect. Treatment with β-catenin or HDAC inhibitors showed a dose dependent growth inhibition, while Wnt3a treatment increased proliferation compared to control. Chemical inhibition of β-catenin decreased CyclinD1 and c-Myc expression levels, while β-catenin activation increased same markers expression.  Genetic KD of CTNNB1 resulted in marked decrease in β-catenin, CyclinD1, C-Myc and AR expression. Treatment of UF cells with HDACis decreased nuclear β-catenin, CyclinD1 and C-Myc expression. Moreover, HDACis induced UF cells apoptosis and cell cycle arrest. Conclusion: β-catenin nuclear-translocation contributes to UF phenotype, β-catenin signaling is modulated by estradiol and HDAC activity.