Volatile organic compounds (VOCs) are important environmental factors because they supply nutrients for microbial cells and mediate intercellular interactions. However, few studies have focused on the effects of VOCs on prokaryotic diversity and community composition. In this study, we examined the relationship between prokaryotic diversity and community composition and the content of VOCs in salt-lake sediments from the Tibet Plateau using amplicon sequencing of the 16S rRNA gene. Results showed that the alpha-diversity indices (Chao1, Shannon, and Simpson) were generally negatively correlated with the content of 36 VOCs (P < 0.05). The prokaryotic communities were significantly driven by multiple VOCs at the lineage-dependent pattern (P < 0.05). Further analysis indicated that VOCs, including 3-methylpyruvate, biuret, isocitric acid, and stearic acid, jointly explained 37.3% of the variations in prokaryotic communities. Supplemental VOCs-pyruvate, biuret, alanine, and aspartic acid-notably decreased the Chao1 and Shannon indices and significantly assembled co-occurrence networks for the bacterial communities in the saline sediments. Together, these results demonstrated that VOCs play a critical role in the regulation of the diversity, compositions, and network structures of prokaryotic communities in saline sediments.