(1) Background: In cardiovascular applications, paclitaxel inhibits smooth muscle cell proliferation and migration and significantly reduces the occurrence of restenosis and target lesion revascularization. However, the cellular effects of paclitaxel in the myocardium are not well understood; (2) Methods: Wistar rats were divided into four groups: control (CTRL), isoproterenol (ISO) treated (1 mg/kg) and two groups treated with paclitaxel (PAC), which was administrated (10 mg/kg/day) for 5 days by gavage/per os alone or in combination (ISO + PAC) 3 weeks after ISO treatment. Ventricular tissue was harvested 24 h later for measurements of heme oxygenase (HO-1), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), NF-κB, TNF-α and myeloperoxidase (MPO); (3) Results: HO-1 protein concentration, HO-1 activity, SOD protein concentration and total glutathione significantly decreased in response to ISO treatment. When PAC was administered in conjunction with ISO, HO-1, SOD concentration and total glutathione were not different from control levels. MPO activity, NF-κB concentration and TNF-α protein concentration were significantly increased in the ISO-only group, while the levels of these molecules were restored when PAC was co-administered; (4) Conclusions: Oral administration of PAC can maintain the expression of important antioxidants, anti-inflammatory molecules, HO-1, SOD and GSH, and suppress the production of TNF-α, MPO and NF-κB, which are involved in myocardial damage. The principal component of this cellular defense seems to be the expression of HO-1.