Morganella psychrotolerans is a psychrotolerant histamine producer and can cause histamine food poisoning via various seafood sources. Autoinducer-2 (AI-2) is a major quorum-sensing (QS) signal molecule recognized and produced by a wide variety of bacteria thereby playing a critical role in regulating the communications and behaviors of various microbes. Our study was investigated the effect of AI-2 on histamine formation by M. psychrotolerans. The results showed that the histamine concentration was increased by the addition of (S)-4,5-dihydroxy-2,3-pentanedione (DPD), the precursor to all AI-2s, in broth culture and in tuna. Based on the integration analysis of transcriptomics and metabolomics, we identified 298 differential expressed genes (DEGs) and 206 differential metabolites (DMs) in the DPD-added group compared with the control group. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the Glycine, serine and threonine metabolism, Histidine metabolism, and ATP-binding cassette (ABC) transporter pathway were significantly co-enriched as shown by the transcriptomics and metabolomics data. Furthermore, AI-2 mediated the increase of histamine formation in the strain mainly through the activated methyl cycle (AMC). AI-2 may mediate the regulation of histamine formation in M. psychrotolerans, involving several regulatory pathways. These results provide new insights into the histamine formation in aquatic products.