A preference for and overconsumption of a high-fat diet (HFD) are common among adolescents and are recognized as risk factors for multiple mental disorders. The protracted maturation of the medial prefrontal cortex (mPFC), a key brain structure that plays a critical role in mental functions that are essential for both developing and mature individuals (including emotional processing, decision making, risk assessment, and creative thinking), during adolescence renders it more vulnerable to the environmental insults experienced during this critical developmental window. However, the effects of HFD consumption during adolescence on mPFC-related behaviours and the underlying mechanisms need to be further investigated. In this study, we observed that mice fed a HFD throughout adolescence developed depressive- and anxiety-like behaviours and distinctively increased risk-avoidance behaviour, accompanied by morphological aberrations of both pyramidal neuron and microglia in the mPFC. The systemic administration of minocycline, a well-known broad-spectrum antibiotic, effectively attenuated the adverse effects of HFD consumption during adolescence on neurobehaviours and the morphology of pyramidal neurons in the mPFC. This study provides new insights into the psychological effects of long-term HFD consumption during adolescence and indicates the existence of a window during which microglial stabilization may be a promising strategy to protect against the HFD consumption-induced increase in the risk of psychiatric disorders.