Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution1-3. Despite gene editing, the immune reactions following xenotransplantation can still cause transplant failure4. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer cells and dendritic cells increased between postoperative day (POD) 10 and 28, concordant with an expansion of IgG and IgA B cell clonotypes and subsequent biopsy-confirmed antibody-mediated rejection (AMR) at POD33. Human T cell frequencies increased from POD14 and peaked between POD33 and POD49 in the blood and xenograft, which coincided with T cell receptor diversification, expansion of a restricted TRBV2 and TRBJ1 clonotype and histological evidence of combined AMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, which aligned with interferon-γ-driven inflammation and a T helper 1-type immune response. There was also evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury marked by S100A6 (ref. 5), SPP1 (also known as osteopontin)6 and COLEC11 (ref. 7) expression at POD21-POD33. Proteomic profiling revealed activation of human and pig complement, with a decreased human component after AMR therapy, in which complement was inhibited. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney and reveal potential immunomodulatory targets for improving xenograft survival.