Abstract Cadmium (Cd) pollution in the farmland has become a serious global issue threatening both human health and plant biomass production. Seashore paspalum (Paspalum vaginatum Sw.), a halophytic turfgrass, has been recognized as a Cd-tolerant species. However, the underlying genetic basis of natural variations in Cd tolerance still remains unknown. This study is possibly the first to apply genome-wide association studies (GWAS) and selective sweep analysis to identify potential Cd stress-responsive genes in P. vaginatum. We identified a total of 89 candidate genes and 656 putative selective sweeps regions. Based on the correlation analysis of differentially expressed metabolites (DEMs) and differentially expressed genes (DEGs), we identified the 55 key genes associated with metabolic changes induced by Cd treatment as the Cd tolerance-related genes. These genes showed significantly higher expression in Cd-tolerant accessions as compared to Cd-susceptive accessions. Therefore, our multi-omics study revealed the molecular and genetic basis of Cd tolerance, which may help develop Cd tolerant crop varieties.