Semaglutide has little hepatic metabolism and is deemed low risk for causing drug-induced liver injury (DILI). We present a case of DILI from the US DILI Network. The case involved a 51-year-old man with type 2 diabetes who presented with jaundice and acute-on-chronic kidney disease 6 months after starting oral semaglutide. His liver injury progressed to biliary cirrhosis, accompanied by nephritis that led to end-stage renal disease. Extensive evaluations including liver and kidney biopsies revealed no alternative etiologies. Cholestatic gene sequencing revealed heterozygosity forand. He eventually underwent combined liver and kidney transplantation.