The Lsc RhoGEF (also known as p115‐RhoGEF) is a GTP exchange factor (GEF), an activator of GTPases of the Rho family. Lsc has a RhoGEF domain specific for Rho GTPase and a regulator of G protein signaling (RGS) domain specific for Gα_12/13 subunits. One G protein receptor that can couple to Gα_12/13 subunits is the receptor for thromboxane A₂ (TXA₂), thromboxane‐prostanoid (called TP), which is highly expressed in immature thymocytes. TXA₂ has been implicated in thymocyte apoptosis. We found that Lsc^–/– mice on a BALB/c background show thymic hyperplasia due to increased numbers of thymocytes and that these numbers further increase with the age of the mice. To investigate a role for Lsc in TXA₂ signaling, we analyzed activation of primary thymocytes by TXA₂ in vitro. TXA₂‐induced apoptosis of double‐positive thymocytes and Rho activation required Lsc, and TXA₂ stimulation of actin polymerization and cofilin phosphorylation required both Lsc and Rho kinase (ROCK). Additionally, in the absence of Lsc, phosphorylation of the survival kinase Akt in response to TXA₂ was greatly enhanced. Together, these data demonstrate that Lsc is essential for mediating TXA₂ signaling involved in apoptosis and actin organization and suggest that TXA₂ regulates thymic cellularity via Lsc.