Cisplatin (CIS) is a widely used chemotherapeutic agent associated with cardiotoxicity. Nanocurcumin (N-CUR), a nano-formulated antioxidant and anti-inflammatory agent, has shown enhanced therapeutic efficacy over native curcumin. This study investigated the cardioprotective effects of N-CUR against CIS-induced cardiotoxicity in rats, focusing on oxidative stress, inflammation, apoptosis, and calcium (Ca2⁺) homeostasis regulators, Ca2⁺ binding protein A1 (S100A1) and sarcoplasmic reticulum Ca2⁺-ATPase 2a (SERCA2a). Male Wistar rats received N-CUR (80 mg/kg) orally for 10 days, while CIS (7 mg/kg, i.p.) was given on day 7. CIS significantly elevated cardiac injury markers and induced myocardial histopathological changes. It increased MDA levels while reducing GSH, SOD, and catalase, indicating oxidative damage. Inflammatory markers including NF-κB p65, iNOS, TNF-α, and IL-6 were markedly upregulated. Apoptosis, marked by upregulated Bax and caspase-3 and decreased Bcl-2, was enhanced. Furthermore, CIS suppressed S100A1 and SERCA2a, disrupting Ca2⁺ homeostasis. N-CUR effectively reversed these changes, restoring antioxidants, suppressing inflammation and apoptosis, and normalizing Ca2⁺-regulating proteins, thereby preserving cardiac integrity. In conclusion, N-CUR protects against CIS-induced cardiotoxicity through antioxidative, anti-inflammatory, and anti-apoptotic mechanisms, as well as by restoring Ca2⁺ homeostasis. These findings support the therapeutic potential of N-CUR as an adjunct treatment to reduce cardiovascular complications in patients receiving CIS-based chemotherapy.