Salt stress impairs plant growth and development, generally resulting in crop failure. Tomato domestication gave rise to a dramatic decrease in salt tolerance caused by the genetic variability of the wild ancestors. However, the nature of artificial selection in reducing tomato salt tolerance remains unclear. Here, we generated and analyzed datasets on the survival rates and sodium (Na+) and potassium (K+) concentrations of hundreds of tomato varieties from wild ancestors to contemporary breeding accessions under high salinity. Genome-wide association studies (GWAS) revealed that natural variation in the promoter region of the putative K+ channel regulatory subunit-encoding gene KSB1 (potassium channel beta subunit in Solanum lycopersicum) is associated with survival rates and root Na+/K+ ratios in tomato under salt stress. This variation is deposited in tomato domestication sweeps and contributes to modified expression of KSB1 by salt-induced transcription factor SlHY5 in response to high salinity. We further found that KSB1 interacts with the K+ channel protein KSL1 to maintain cellular Na+ and K+ homeostasis, thus enhancing salt tolerance in tomato. Our findings reveal the crucial role of the SlHY5-KSB1-KSL1 module in regulating ion homeostasis and salt tolerance during tomato domestication, elucidating that selective pressure imposed by humans on the evolutionary process provides insights into further crop improvement.