This study compared the potential ability of multinomial echocardiographic parameters in early detection, prediction and combined diagnosis of antineoplastic-related cardiotoxicity. Male Balb/c mice were repeatedly administered with low doses of epirubicin (6 × 3 mg/kg; n = 20) to induce cardiac injury or with placebo as control (n = 10). Conventional and strain parameters as well as myocardial performance index (MPI) were analyzed at baseline, 1 day after the second, fourth and sixth cycle, and 12 days after completion of chemotherapy (as follow-up) by a high-resolution rodent ultrasound machine. After the experiment, serum cTnI levels were measured, and myocardial injury was evaluated by histological analyses. Thirteen mice developed cardiotoxicity after epirubicin exposure. Global longitudinal (GLS), radial strain (GRS) and longitudinal strain rate (LSR) were markedly decreased (all P ≤ 0.01) and MPI was increased (P ≤ 0.05) at the completion of treatment compared with baseline values. GLS expressed the best correlations with myocardial pathological injury, especially with collagen content (ρ = − 0.68, P < 0.01). Additionally, GLS and MPI were associated with serum cTnI levels. A > 9.5% decrease in GLS from baseline to the fourth cycle of chemotherapy could predict future cardiotoxicity (odds ratio = 0.331, P < 0.05). GLS (cutoff value, − 15.16%) combined with MPI (cutoff value, 0.64) could improve the accuracy of diagnosing cardiotoxicity (sensitivity, 92%; specificity, 87%). GLS was the only predictor of cardiotoxicity. GLS combined with MPI may provide a noninvasive and accurate method for the early detection of cardiotoxicity.