Background:&nbsp;Bevacizumab is a widely used anti-VEGF-A therapy in oncology and ophthalmology, valued for its potent anti-angiogenic effects across cancer and ocular diseases. Beyond angiogenesis, growing evidence suggests that VEGF-A also contributes to neuronal homeostasis, including autophagy regulation, synaptic plasticity, and nociceptive processing. These nonvascular actions raise the possibility that bevacizumab may influence central mechanisms of pain control, particularly in patients requiring opioid analgesics. Whether bevacizumab disrupts morphine antinociception through modulation of mPFC neuronal TSC1-mTOR-autophagy signalling remains unknown.<br><br>Methods:&nbsp;Here we combined a small observational clinical cohort with behavioral pharmacology, conditional Vegfa&nbsp;deletion, quantitative proteomics, molecular and ultrastructural analyses, whole-cell electrophysiology, chemogenetics and in vivo&nbsp;fiber photometry to examine how VEGF-A blockade affects morphine responses in the medial prefrontal cortex (mPFC).<br><br>Findings:&nbsp;Patients receiving bevacizumab with morphine required progressively higher morphine doses than those receiving morphine alone. In mice, bevacizumab reduced morphine potency, accelerated tolerance, and increased abnormal mPFC neuronal activity during morphine treatment, effects mimicked by local Vegfa&nbsp;deletion in the mPFC. Mechanistically, VEGF-A blockade caused neuron-specific downregulation of TSC1, accompanied by mTOR/RPS6 activation and impaired late-stage autophagic flux. Bevacizumab also blunted morphine-induced suppression of excitability, synaptic activity, and nociception-evoked calcium signals, predominantly in VGluT1-positive neurons. Restoring TSC1 or inhibiting mTOR with rapamycin partially rescued these defects and improved analgesia.<br><br>Interpretation:&nbsp;When considered alongside the widespread clinical use of bevacizumab, these findings suggest that mPFC VEGF-A-TSC1-mTOR-autophagy signalling may be a clinically relevant mechanism underlying impaired morphine analgesia during anti-angiogenic therapy.