Polyamines act as protective compounds directly protecting plants from stress-related damage, while also acting as signaling molecules to participate in serious abiotic stresses. However, the molecular mechanisms underlying these effects are poorly understood. Here, we utilized metabolome genome-wide association study to investigate the polyamine content of wild and cultivated tomato accessions, and we discovered a new gene cluster that drove polyamine content during tomato domestication. The gene cluster contains two polyphenol oxidases (SlPPOE and SlPPOF), two BAHD acyltransferases (SlAT4 and SlAT5), a coumaroyl-CoA ligase (Sl4CL6), and a polyamine uptake transporter (SlPUT3). SlPUT3 mediates polyamine uptake and transport, while the five other genes are involved in polyamine modification. Further salt tolerance assays demonstrated that SlPPOE, SlPPOF, and SlAT5 overexpression lines showed greater phenolamide accumulation and salt tolerance as compared with wild-type (WT). Meanwhile, the exogenous application of Spm to SlPUT3-OE lines displayed salt tolerance compared with WT, while having the opposite effect in slput3 lines, confirms that the polyamine and phenolamide can play a protective role by alleviating cell damage. SlPUT3 interacted with SlPIP2;4, a H2O2 transport protein, to maintain H2O2 homeostasis. Polyamine-derived H2O2 linked Spm to stress responses, suggesting that Spm signaling activates stress response pathways. Collectively, our finding reveals that the H2O2-polyamine-phenolamide module coordinately enhanced tomato salt stress tolerance and provide a foundation for tomato stress-resistance breeding.