Background <p>Isoprenaline-mediated cardiac hypertrophy has been implicated in the activation of immune cells leading to inflammation, oxidative stress and altered electrocardiogram pattern. Meanwhile, therapy with lisinopril or vincristine has shown promising therapeutic effects when administered singly. However, there is paucity of information on the possible therapeutic effect on the combined therapy.</p> Methods <p>Cardiac hypertrophy was induced in animals with 1&#xa0;mg/kg of isoprenaline for 14 days and thereafter treated with vincristine (25&#xa0;µg/kg) in a 6-day cycle with 2 days off in between each cycle and/or lisinopril 20&#xa0;mg/kg orally for consecutive 28 days. Electrocardiography as well as blood pressure measurement was done before euthanasia and thereafter, the heart sample was collected and processed for biochemical and histological evaluation.</p> Results <p>The findings from this study indicate that isoprenaline exposure led to dyslipidemia and a malfunctioning heart contractile system, which in turn triggered oxidative stress and activation of inflammatory pathways. Anomalies related to abnormal histoarchitecture and hypertrophic phenotypes were observed together with abnormal electrical and mechanical activity. The hypertrophic alterations were lessened by vincristine or lisinopril, and the combination of the two medications reverses the hypertrophy of the heart caused by isoprenaline.</p> Conclusion <p>Co-administration of vincristine and lisinopril reversed cardiac hypertrophy by modulating contractile proteins and inhibiting the activation of executioner caspase-3 and oxido-inflammatory mediator’s activation.</p>