Signaling from the activin/transforming growth factor β (TGFβ) family of cytokines is a tightly regulated process. Disregulation of TGFβ signaling is often the underlying basis for various cancers, tumor metastasis, inflammatory and autoimmune diseases. In this study, we identify the protein G‐coupled receptor kinase 2 (GRK2), a kinase involved in the desensitization of G protein‐coupled receptors (GPCR), as a downstream target and regulator of the TGFβ‐signaling cascade. TGFβ‐induced expression of GRK2 acts in a negative feedback loop to control TGFβ biological responses. Upon TGFβ stimulation, GRK2 associates with the receptor‐regulated Smads (R‐Smads) through their MH1 and MH2 domains and phosphorylates their linker region. GRK2 phosphorylation of the R‐Smads inhibits their carboxyl‐terminal, activating phosphorylation by the type I receptor kinase, thus preventing nuclear translocation of the Smad complex, leading to the inhibition of TGFβ‐mediated target gene expression, cell growth inhibition and apoptosis. Furthermore, we demonstrate that GRK2 antagonizes TGFβ‐induced target gene expression and apoptosis ex vivo in primary hepatocytes, establishing a new role for GRK2 in modulating single‐transmembrane serine/threonine kinase receptor‐mediated signal transduction.