Estrogens are important regulators of neuronal cell morphology and this is thought to be critical for gender-specific differences in brain function and dysfunction. Dendritic spine formation is dependent on actin remodeling by the WASP-family verprolin homologous (WAVE1) protein, that controls actin polymerization through the actin-related protein 2/3 (Arp2/3) complex. Emerging evidence indicates that estrogens are effective regulators of the actin cytoskeleton in various cell types via rapid, extra-nuclear signaling mechanisms. We here show that 17-estradiol (E2) administration to rat cortical neurons leads to phosphorylation of WAVE-1 on the serine residues 310, 397 and 441 and to WAVE1 redistribution toward the cell membrane, at sites of dendritic spine formation. WAVE1 phosphorylation is found to be triggered by a G_i/G protein-dependent, rapid extra-nuclear signaling of estrogen receptor (ER) to c-Src and to the small GTPase Rac1. Rac1 recruits the cyclin-dependent kinase (Cdk5) which directly phosphorylates WAVE1 on the three serine residues. Following WAVE1 phosphorylation by estradiol, the Arp2/3 complex concentrates at sites of spine formation, where it triggers the local reorganization of actin fibres. In parallel, estradiol recruits a G₁₃-dependent pathway to RhoA and ROCK-2, leading to activation of actin remodeling via the actin-binding protein, moesin. Silencing of WAVE1 or of moesin abrogates the increase in dendritic spines induced by E2 in cortical neurons. In conclusion, our findings indicate that the control of actin polymerization and branching via moesin or WAVE1 is a key function of ER in neurons which may be particularly relevant for the regulation of dendritic spines.