GABAergic neurotransmission generates two types of inhibitions: the transient activation of synaptic GABA receptors, or phasic inhibition, which elicits inhibitory postsynaptic currents, and the activation of extrasynaptic GABA receptors by “ambient” GABA which causes a persistent, “tonic”, inhibition that finely tunes cellular excitability of target neurons. Change in GABA synaptic efficacy is a crucial mechanism that underlies experience-dependent modifications of brain function. Several forms of GABA synaptic plasticity require retrograde signaling by endocannabinoids (eCB) through the activation of presynaptic CB1 receptor. Whereas the molecular mechanisms of eCB-dependent presynaptic regulation of GABAergic synaptic strength have been widely reported, little is known about the potential control of eCB signalling on extrasynaptic GABA inhibition. By using whole-cell patch-clamp recordings, we demonstrated that brief depolarization of cortical pyramidal neurons is associated with a transient increase in tonic GABA current that is dependent upon CB1 receptor activity and 2-AG signaling. Moreover, we showed that this depolarization-dependent plasticity of tonic inhibition requires intracellular neurosteroid action since the pharmacological inhibition of steroid production completely abolished this phenomenon. Here we provide evidence of a novel form of eCB-dependent plasticity of tonic inhibition that is likely to have a key role in finely tuning the excitatory-inhibitory balance in the mouse neocortex.