Tilmicosin (Til), an effective macrolide antibiotic, is widely used against respiratory diseases in livestock; however, its treatment is associated with cardiac tissue impairments. In this study, the ethanolic extract of Moringa oleifera (MO) leaves was investigated at two doses (400 and 800 mg/kg body weight [bw], orally) to determine its role in counteracting the effects of Til treatment (75 mg/kg bw) on the cardiac tissue in rats, exploring the oxidative stress-mediated damage and apoptosis. A high dose of MO ethanolic extract elicits considerable changes in the body weight, reduces the mortality rate, neutralizes the impaired cardiac injury markers, improves antioxidant endpoints (total antioxidant capacity, superoxide dismutase, catalase activity, and reduced glutathione level). Also it attenuates the oxidative stress indices (total reactive oxygen species, 8-hydroxy-2-deoxyguanosine, lipid peroxides [malondialdehyde], and protein carbonyl levels) that are associated with Til injection. The co-administration of MO ethanolic extract with Til considerably modulates the expression of apoptosis pathway-encoding genes (Bcl-2, caspase-3, Bax, p53, apoptosis-inducing factor, and Apaf-1), particularly in the high-dose group. Our results support that the concurrent administration of MO ethanolic extract with Til at a dose of 800 mg/kg bw increases the protective activity of the antioxidant system and delays or slows the pathological development of cardiotoxicity mediated by Til injection.