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MicroRNAs (miRNAs) play crucial roles in regulating gene expression and have been implicated in the pathophysiology of depression. Among them, miR-124-3p is one of the most abundant brain-enriched miRNAs and has emerged as a potential therapeutic target for mood disorders. This study aimed to evaluate the antidepressant-like effects of an acute administration of miR-124-3p and to identify associated molecular and neuronal changes across key brain regions. Female C57BL/6 mice received intracerebroventricular injections of a miR-124-3p mimic or a control oligonucleotide. Affective-like behavioural responses were assessed using the Porsolt swim test (PST) and the light-dark box test (LDB). Proteomic alterations in the hippocampus, hypothalamus and prefrontal cortex were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and stress-related neuronal activity was evaluated using c-Fos immunofluorescence. Mice treated with the miR-124-3p mimic exhibited reduced immobility in the PST, indicative of an antidepressant-like effect and enhanced active stress coping. Proteomic profiling revealed region-specific changes, including downregulation of immune- and stress-related proteins in the hypothalamus and hippocampus, and upregulation of synaptic and metabolic proteins in the prefrontal cortex. c-Fos analyses showed decreased stress-induced neuronal activation in the hypothalamic paraventricular and periventricular nuclei, alongside increased activity in the hippocampal dentate gyrus. Collectively, these findings suggest that miR-124-3p mimic treatment is associated with antidepressant-like effects by reducing neuroimmune activation and enhancing neuronal plasticity. Our results support a model in which miR-124-3p promotes stress resilience through coordinated modulation of inflammatory and plasticity-related processes across distinct brain circuits.