Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased oscillation of clock negative regulatory loop, as well as a phase shift of Bmal1 expression in the medial prefrontal cortex (mPFC) of a mouse model of depression (depression-like behavior and anhedonia induced by daily 10 min swim sessions for 5 consecutive days). Selective disruption of mPFC clockwork with viral Bmal1KO in CaMK2a excitatory neurons blocks the development of depressive-like phenotype in our model of depression. A recent report implicates BMAL1 in the regulation of the synaptic plasticity protein Homer1a, which is implicated in the antidepressant mechanisms. Pharmacological potentiation of clock positive modulator RORα/γ by the agonist SR1078 elicited antidepressant-like effects, upregulating Bmal1 expression and the plasticity protein Homer1a. SR1078-treated mice WT mice also exhibited elevated expression of AMPA receptors, which directly links the circadian clock to synaptic plasticity mechanisms via Homer1a. We then studied the effects of SR1078 on our CaMK2a-Bmal1KO model of mPFC, which showed no effect on mood or Homer1a expression, highlighting the importance of Bmal1. Then, we investigated the necessity of Homer1a induction for the observed SR1078-mediated antidepressant effect. In vivo KD of Homer1a with siRNA in mPFC blocked the antidepressant effect of SR1078. Taken together, these results demonstrate that the antidepressant effects of RORα/γ agonism in the CDM model are mediated by Bmal1 in the mPFC and Homer1a-dependent.