We examined whether CB₁ receptors in smooth muscle conform to the signaling pattern observed with other G_i-coupled receptors that stimulate contraction via two Gβ-dependent pathways (PLC-β3 and PI 3-kinase/integrin-linked kinase). Here we show that the anticipated Gβ-dependent signaling was abrogated. Except for inhibition of adenylyl cyclase via Gα_i, signaling resulted from Gβ-independent phosphorylation of CB₁ receptors by GRK5, recruitment of β-arrestin1/2, and activation of ERK1/2 and Src kinase. Neither uncoupling of CB₁ receptors from G_i by PTx or G_i minigene, nor expression of a Gβ-scavenging peptide had any effect on ERK1/2 activity. The latter was abolished in muscle cells expressing β-arrestin1/2 siRNA. CB1 receptor internalization and both ERK1/2 and Src kinase activities were abolished in cells expressing kinase-deficient GRK5(K215R). Activation of ERK1/2 and Src kinase endowed CB₁ receptors with the ability to inhibit concurrent contractile activity. We identified a consensus sequence (¹⁰²KSPSKLSP¹⁰⁹) for phosphorylation of RGS4 by ERK1/2 and showed that expression of a RGS4 mutant lacking Ser¹⁰³/Ser¹⁰⁸ blocked the ability of anandamide to inhibit acetylcholine-mediated PI hydrolysis or enhance Gα_q:RGS4 association and inactivation of Gα_q. Activation of Src kinase by anandamide enhanced both M-RIP:RhoA and M-RIP:MYPT1 association and inhibited Rho kinase activity leading to increase of MLC phosphatase activity and inhibition of sustained muscle contraction. Thus, unlike other G_i-coupled receptors in smooth muscle, CB₁ receptors did not engage Gβ but signaled via GRK5/beta-arrestin activation of ERK1/2 and Src kinase: ERK1/2 accelerated inactivation of Gα_q by RGS4, and Src kinase enhanced MLC phosphatase activity leading to inhibition of ACh-stimulated contraction.