Fermented chili products are popular traditional fermented foods around the world. However, differences in microbial communities in fermented chilies from different regions and how they affect the flavor compounds in chili fermentation have not been reported. In this study, the dynamics of flavor compounds and microbial communities in fermented chilies from Sichuan, Guizhou, and Hunan were systematically investigated by macro-genome sequencing, solid phase microextraction-gas chromatograph-mass spectrometry (SPME-GC-MS), electronic nose, and electronic tongue techniques. Simultaneously, the microbial metabolic mechanisms and the relationship between flavor compounds and microbiome were unraveled through staged and simulated fermentation analysis. The results showed that 53 chemical odorants, including alcohols, esters, aldehydes, and acids, were identified as chemical markers to differentiate the regional samples. Twelve microbial species, including Staphylococcus xylosus, Unclassified staphylococcus species, Weissella confusus, Lactococcus cremoris, Lactococcus garvieae, Lactiplantibacillus sakei, Pediciococcus propionicigenes, Pediciococcus idahonensis, Pediciococcus aciditolerans, Nocardioides antri, Debaryomyces hansenii, and Colletotrichum scovillei, were identified as microbial markers to differentiate the regional samples. Correlation analysis showed that Lactobacillaceae was associated with fruity, floral, spicy, and fatty aromas. The electronic nose and tongue analysis results showed that 9 flavor and 8 taste indicators significantly differed between regional samples (P < 0.05). Additionally, flavor compounds and microbial diversity were robust under initial selection stress and showed higher diversity under metabolome-microbiome interactions. Importantly, simulated fermentation confirmed that metabolome-microbiome interactions drove the shift in microbial structure, metabolism, and flavor in regionally fermented chilies. These results provide insights into the succession of microbial communities and the formation of flavor compounds in chili fermentation, which may enable the future replication of fermented foods with the same flavor.