This study analyzed the spatiotemporal heterogeneity of metastatic small bowel adenocarcinoma (SBA) with peritoneal involvement by examining genomic profiles of six SBAs and their corresponding peritoneal metastases using next-generation sequencing. Four cases had synchronous peritoneal metastases, showing complete genomic concordance with the primary tumors. In contrast, one of the two cases with metachronous peritoneal metastases developed an additional KRAS mutation compared to the paired primary, shifted from moderately to poorly differentiated morphology, and exhibited mismatch-repair deficiency by immunohistochemistry, while remaining microsatellite stable by NGS. These findings suggest interlesional molecular heterogeneity in SBA and emphasize the need for re-biopsies in precision oncology for metachronous metastases.