Acrylamide (ACR), a common environmental and food contaminant, can cause neurotoxicity and increase the risk of neurodegenerative diseases. While the neurotoxicity induced by high-dose ACR exposure in occupational workers is evident, the potential adverse effects of low-dose daily exposure remain a subject of debate. In this present study, we aim to explore whether low-dose ACR induces neurotoxicity based on the interactions between microglia and neurons. Results demonstrated that low-dose ACR did not significantly impair mitochondrial homeostasis in SH-SY5Y cells, but induced microglial polarisation towards the M1 pro-inflammatory phenotype at this concentration. Interestingly, the supernatants from ACR pre-activated BV2 microglia were observed to trigger mitochondrial dysfunction, induce autophagy, and disrupt energy metabolism in SH-SY5Y cells, whose effects were not observed in cells solely treated with ACR. Furthermore, muscone, acting as an inhibitor of inflammatory factors, successfully ameliorated the activation of microglia induced by low-dose ACR and notably downregulated the expression levels of IL-1β, IL-6, and TNF-α. In an additional effect, muscone reversed the expression trends of P62 and LC3 proteins, which were perturbed by the activation of microglia in SH-SY5Y cells. In conclusion, our results proved that low-dose ACR induced mitochondrial autophagy and energy metabolism disturbance in SH-SY5Y cells via BV2 microglial activation, which might be significantly influenced by the release of pro-inflammatory factors. Our study emphasized the crucial role of microglia-neuronal interactions, providing novel insights for understanding low-dose ACR induced neurotoxicity.