Statins have been associated with a range of adverse effects, collectively termed statin-associated muscle symptoms (SAMS). Currently, there are no reliable biomarkers available for precise clinical diagnosis. Since urine is not regulated by homeostatic mechanisms, it reflects early alterations, positioning it as an optimal source for biomarker discovery. We thus undertook an examination of the proteomic alterations in urine that are associated with SAMS. In this research, a SAMS rat model was created through intragastric administration of simvastatin (80 mg/kg). Biochemical assessments and haematoxylin and eosin staining techniques were utilized to determine the degree of muscle damage. The urine proteome was analyzed on days 3, 6, 9, and 14 utilizing liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The differential proteins identified on day 14 of SAMS were associated with glycolysis/gluconeogenesis, pyruvate metabolism, metabolism of reactive oxygen species, and apoptosis, which are all implicated in the pathological mechanism of SAMS. Among the 14 differential proteins identified on day 3, fibrinogen gamma chain (FIBG), osteopontin (OSTP), and C-reactive protein (CRP) were associated with muscle injury, whereas EH domain-containing protein 1 (EHD1), cubilin (CUBN), and fibronectin (FINC) were implicated in the pathogenic mechanisms of SAMS. This chapter focuses on the early pathological changes and early diagnostic biomarkers of SAMS.