Aortic disease encompasses life-threatening conditions such as aortic aneurysm and dissection, which are associated with high prevalence, morbidity, and mortality. The complement system, a key component of innate immunity, not only defends against pathogens but also maintains tissue homeostasis. Recent discoveries have expanded its role beyond immunity, linking complement dysregulation to numerous diseases and positioning it as a target for pharmacotherapy. Complement-based treatments for precision medicine are emerging, with several pharmaceuticals either already approved or under investigation. In aortic disease, complement activation and dysregulation have unveiled novel mechanisms and clinical implications. Human and experimental studies suggest that all three complement pathways contribute to disease pathophysiology. The complement system induces direct cellular damage via the membrane attack complex, as well as matrix metalloproteinase (MMP)-associated tissue damage by promoting MMP-2 and MMP-9 expression. The anaphylatoxins C3a and C5a exacerbate disease by recruiting immune cells and triggering pro-inflammatory responses. Examples include neutrophil extracellular trap formation and cytokine release by polymorphonuclear neutrophils. These findings highlight the complement system as a promising novel diagnostic and therapeutic target in aortic disease with potential for individualized treatment. However, gaps remain, emphasizing the need for standardized multisite preclinical studies to improve reproducibility and translation. Biomarker studies must also be validated across diverse patient cohorts for clinical applicability. This review examines current knowledge regarding complement in aortic disease, aiming to evaluate its potential for innovative diagnostic and personalized treatment strategies.