Semaglutide, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), has demonstrated remarkable therapeutic efficacy in managing type 2 diabetes (T2D) and obesity in recent years, emerging as a focal point in clinical research. However, with the expansion of its clinical application, there is increasing evidence that semaglutide can cause multisystem adverse reactions, leading to reduced patient compliance and safety. Recent research findings indicate that adverse events associated with semaglutide involve pathological changes across multiple systems (digestive, cardiovascular, neurological, reproductive, immune and respiratory) and organs (liver, kidneys, thyroid and retina). The precise mechanisms underlying these effects remain incompletely characterized, hindering early detection and targeted intervention in clinical practice. This review integrates evidence from preclinical studies, randomized controlled trials (RCTs), and real-world data to systematically evaluate the safety profile of GLP-1RAs, with semaglutide as the primary focus. It elucidates the biological mechanisms underlying organ/system-specific adverse effects broadly applicable to the GLP-1RA class. Furthermore, we propose a stratified management framework to guide personalized treatment strategies aligned with precision medicine principles, aiming to optimize the dynamic equilibrium between therapeutic efficacy and safety risks.