Sleep fragmentation (SF) exacerbates myocardial ischemia-reperfusion (MI/RI) injury by promoting copper overload in cardiomyocytes. This study shows that 16 weeks of SF in male mice leads to elevated copper levels in the heart and worsens MI/RI with increased cuproptosis and apoptosis. Mechanistically, SF promotes sympathetic overactivity, increases sympathetic nerve terminal germination, and raises norepinephrine levels in cardiac tissue, which inhibits VPS35 expression and impairs ATP7A-related copper transport, leading to copper overload. Copper overload further exacerbates cuproptosis and apoptosis, which can be rescued by sympathetic nerve excision or copper chelation. The study elucidates a molecular mechanism by which sleep disorders aggravate myocardial injury and suggests potential therapeutic targets. Sleep disorders are associated with increased risk and mortality of heart disease. Experimental models confirm the detrimental effects of sleep deprivation on cardiac injury. Myocardial injury is linked to ion homeostasis, particularly copper homeostasis, which is crucial for various physiological functions. Copper overload activates apoptosis and cuproptosis, a newly identified copper-dependent cell death. Sympathetic hyperactivity is a key feature of both sleep disorders and cardiovascular diseases. This study established a mouse model of MI/RI exacerbated by SF and a copper overload model in HL-1 cells to investigate the effects of SF on cardiac copper metabolism and underlying mechanisms. Chronic SF exacerbated MI/RI and induced cardiomyocyte cuproptosis and apoptosis. SF increased copper levels in the myocardium, with no significant differences in other metals. Copper transporters Slc31a and ATP7A are involved in copper ion transport. SF downregulated Slc31a and upregulated ATP7A, leading to copper overload. Sympathetic hyperactivity increased NE levels, which induced copper overload. NE treatment increased intracellular copper levels and blocked copper transport, leading to cuproptosis. VPS35 inhibition impaired copper transport, causing copper overload. VPS35 overexpression improved copper transport and rescued cuproptosis. Superior cervical ganglionectomy (SCGx) rescued copper overload and improved MI/RI in mice with SF. SCGx restored VPS35 and ATP7A expression and normalized myocardial copper levels. SCGx alleviated DLAT oligomerization, reduced lipoylated protein levels, and decreased HSP70 expression. Copper chelation with TTM reduced myocardial copper levels and improved MI/RI outcomes. These findings suggest that copper overload plays a key role in SF-induced MI/RI. The study highlights the role of sympathetic hyperactivity in copper overload and myocardial injury. Copper overload activates cuproptosis and apoptosis, which can be mitigated by targeting copper transport. The findings suggest that targeting copper metabolism may be a potential therapeutic strategy for sleep disorder-related myocardial injury. The study also identifiesSleep fragmentation (SF) exacerbates myocardial ischemia-reperfusion (MI/RI) injury by promoting copper overload in cardiomyocytes. This study shows that 16 weeks of SF in male mice leads to elevated copper levels in the heart and worsens MI/RI with increased cuproptosis and apoptosis. Mechanistically, SF promotes sympathetic overactivity, increases sympathetic nerve terminal germination, and raises norepinephrine levels in cardiac tissue, which inhibits VPS35 expression and impairs ATP7A-related copper transport, leading to copper overload. Copper overload further exacerbates cuproptosis and apoptosis, which can be rescued by sympathetic nerve excision or copper chelation. The study elucidates a molecular mechanism by which sleep disorders aggravate myocardial injury and suggests potential therapeutic targets. Sleep disorders are associated with increased risk and mortality of heart disease. Experimental models confirm the detrimental effects of sleep deprivation on cardiac injury. Myocardial injury is linked to ion homeostasis, particularly copper homeostasis, which is crucial for various physiological functions. Copper overload activates apoptosis and cuproptosis, a newly identified copper-dependent cell death. Sympathetic hyperactivity is a key feature of both sleep disorders and cardiovascular diseases. This study established a mouse model of MI/RI exacerbated by SF and a copper overload model in HL-1 cells to investigate the effects of SF on cardiac copper metabolism and underlying mechanisms. Chronic SF exacerbated MI/RI and induced cardiomyocyte cuproptosis and apoptosis. SF increased copper levels in the myocardium, with no significant differences in other metals. Copper transporters Slc31a and ATP7A are involved in copper ion transport. SF downregulated Slc31a and upregulated ATP7A, leading to copper overload. Sympathetic hyperactivity increased NE levels, which induced copper overload. NE treatment increased intracellular copper levels and blocked copper transport, leading to cuproptosis. VPS35 inhibition impaired copper transport, causing copper overload. VPS35 overexpression improved copper transport and rescued cuproptosis. Superior cervical ganglionectomy (SCGx) rescued copper overload and improved MI/RI in mice with SF. SCGx restored VPS35 and ATP7A expression and normalized myocardial copper levels. SCGx alleviated DLAT oligomerization, reduced lipoylated protein levels, and decreased HSP70 expression. Copper chelation with TTM reduced myocardial copper levels and improved MI/RI outcomes. These findings suggest that copper overload plays a key role in SF-induced MI/RI. The study highlights the role of sympathetic hyperactivity in copper overload and myocardial injury. Copper overload activates cuproptosis and apoptosis, which can be mitigated by targeting copper transport. The findings suggest that targeting copper metabolism may be a potential therapeutic strategy for sleep disorder-related myocardial injury. The study also identifies