Various experimental and clinical studies strongly support a cigarette smoke-heart disease association and suggest possible mechanisms, unfortunately, the involvement of genetic modulations remain unexplored. Thus, the main aim of the current study was to evaluate the effects of sub-chronic cigarette smoke exposure on the mRNA expression of cardiac hypertrophy genes, cytochrome P450 (CYP) enzymes, and the oxidative stress markers in heart rats. For this purpose, Wistar albino rats were exposed to increasing doses of passive cigarette smoke 2, 4, 8, and 24 cigarettes per day for 7 consecutive days. The mRNA expression of fifteen cardiac genes was determined using real-time polymerase chain reaction. Our results showed that the levels of hypertrophic genes; atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain were significantly induced, whereas the anti-hypertrophic gene α-myosin heavy chain was dramatically inhibited, in heart tissues of passive-smoke-exposed groups compared with normal-control groups. This was accompanied with a significant induction of CYP enzymes; CYP1A1, CYP2C11, CYP2E1, and CYP3A2, and the expression of oxidative stress genes, heme oxygenase 1, catalase, cyclooxygenase, and glutathione S-Transferase. The ability of cigarette smoke to induce cardiac hypertrophic genes, CYPs enzymes, and oxidative stress, collectively explore the molecular mechanism of cigarette smoke-induced cardiac diseases and brings further investigative attention to the public health issue of the injurious effects of chronic passive smoke exposure. In conclusion, sub-chronic environmental tobacco smoke exposure increases the incidence of cardiovascular diseases through modulation of cardiac genes.