Freshwater snails are obligate intermediate hosts for the transmission of schistosomiasis, one of the world's most devastating parasitic diseases. To decipher the mechanisms underlying snail resistance to schistosomes, recombinant inbred lines (RILs) were developed from two well-defined homozygous lines (iM line and iBS90) of the snail Biomphalaria glabrata. Whole-genome sequencing (WGS) was used to scan the genomes of 46 individual RIL snails, representing 46 RILs, half of which were resistant or susceptible to Schistosoma mansoni. Genome-wide association study (GWAS) and bin marker-assisted quantitative trait loci (QTLs) analysis, aided by our chromosome-level assembled genome, were conducted. A small genomic region (∼3 Mb) on chromosome 5 was identified as being associated with schistosome resistance, designated the B. glabrata schistosome resistance region 1 (BgSRR1). This study, built on our recently developed genetic and genomic resources, provides valuable insights into anti-schistosome mechanisms and the future development of snail-targeted biocontrol programs for schistosomiasis.