Anthracyclines such as doxorubicin (dox) are effective chemotherapeutic agents frequently used in adolescents and young adults (AYAs) with cancer but are associated with cardiotoxicity. Mitigation of cardiac late effects through modifiable behaviors has global and cost-effective benefits, but parameters influencing potential benefit remain unclear. Here, we investigated the impact of sucrose consumption on dox-induced cardiotoxicity and senescence in vivo. Male and female p16/3MR transgenic mice were provided normal (NSW, 0%) or high (HSW, 45%) sucrose water and treated with dox (2.5 mg/kg, tail vein ×4 doses). Cardiac function was assessed by echocardiography to measure ejection fraction (EF) and fractional shortening (FS). Cardiac miR-1a and miR-499 expression were quantified by qRT-PCR, and senescent cell accumulation was visualized in heart tissue by red fluorescent protein (RFP) signal. High sucrose intake worsened dox-associated reductions in ejection fraction, with the HSW + dox group showing the greatest functional decline, a pattern that was statistically significant at 4 weeks (p = 0.0187) and 6 weeks (p = 0.0353) post-treatment. Notably, high sucrose alone reduced EF relative to NSW controls, indicating diet-induced impairment of cardiac function. Dox treatment elevated biomarkers of myocardial stress (miR-1a and miR-499) in cardiac tissue, and high sucrose alone produced comparable upregulation. Senescence, as measured by RFP fluorescence, increased in both dox- and sucrose-exposed hearts. Interestingly, the HSW + dox group demonstrated the highest RFP signal, compared to both dox and diet controls, indicating a synergistic enhancement of senescence, suggesting that molecular senescence markers may capture early injury preceding functional decline. High dietary sucrose both amplifies and independently impairs cardiac function and increases senescence, with combined sucrose and dox exposure promoting the strongest EF reduction and senescence elevation. These findings underscore the contribution of sucrose consumption to anthracycline-associated cardiac injury and support the investigation of dietary modulation as a potential strategy to mitigate long-term cardiac damage.