Here we present the paleopathological profiles of two young adult males, identified as brothers through ancient DNA analysis, who were buried together beneath the floor of an elite early Late Bronze Age I (ca. 1550–1450 BC) domestic structure at the urban center of Megiddo (modern Israel). Both individuals displayed uncommon morphological variants related to developmental conditions, and each exhibited extensive bone remodeling consistent with chronic infectious disease. Additionally, one brother had a healed fracture of the nose, as well as a large square piece of bone cut from the frontal bone (cranial trephination). We consider the potential etiologies for the appearance of the skeletal anomalies and lesions. Based on the bioarchaeological context, we propose that a shared epigenetic landscape predisposed the brothers to acquiring an infectious disease and their elite status privileged them enough to endure it. We then contextualize these potential illnesses and disorders with the trephination procedure. The infrequency of trephination in the region indicates that only selected individuals could access such a procedure, and the severity of the pathological lesions suggests the procedure was possibly intended as curative to deteriorating health. Ultimately, both brothers were buried with the same rites as others in their community, thus demonstrating their continued integration in society even after death.