Chicoric acid (CA), a major nutraceutical component of a typical Mediterranean vegetable, chicory, possesses excellent antioxidant and anti-inflammatory bioactivities. This work aimed to elucidate the effects of CA on neuron survival against inflammation and the underlying molecular mechanisms. Results demonstrated that CA promoted SH-SY5Y cells’ autophagic vesicle formation, up-regulated autophagic elongation phase related gene expressions, and inhibited apoptosis stimulated by microglial conditioned culture medium (MCM). In addition, CA significantly improved mitochondrial function and regulated redox homeostasis related signaling pathways such as MAPKs and PI3K/AKT. MCM with CA notably increased the expressions of PGC-1α, SIRT1 and enhanced the phosphorylation of AMPK, promoting energy metabolism. On the other hand, the underlying mechanisms of the intervention of CA in MCM-induced cell apoptosis were partly due to its direct protective effect on SH-SY5Y cells and inhibition of microglial inflammatory factor release. This establishes a theoretical foundation for neuro-nutrition intervention studies of natural functional food components, and provides new clues for developing health foods containing CA.