Cigarette smoking worsens the health of hypertensive patients. However, less is known about the actions and underlying mechanisms of waterpipe smoke (WPS) in hypertension. Therefore, we evaluated the effects of WPS inhalation in mice made hypertensive (HT) by infusing angiotensin II for six weeks. On day 14 of the infusion of angiotensin II or vehicle (normotensive; NT), mice were exposed either to air or WPS for four consecutive weeks. Each session was 30 min/day and 5 days/week. In NT mice, WPS increased systolic blood pressure (SBP) compared with NT air-exposed group. SBP increase was elevated in HT+WPS group versus either HT+air or NT+WPS. Similarly, the plasma levels of brain natriuretic peptide, C-reactive protein, 8-isoprostane and superoxide dismutase were increased in HT+WPS compared with either HT+air or NT+WPS. In the heart tissue, several markers of oxidative stress and inflammation were increased in HT+WPS group vs the controls. Furthermore, mitochondrial dysfunction in HT+WPS group was more affected than in the HT+air or HT+WPS groups. WPS inhalation in HT mice significantly increased cardiac DNA damage, cleaved caspase 3, expression of the autophagy proteins beclin 1 and microtubule-associated protein light chain 3B, and phosphorylated nuclear factor κ B, compared with the controls. Compared with HT+air mice, heart histology of WPS-exposed HT mice showed increased cardiomyocyte damage, neutrophilic and lymphocytic infiltration and focal fibrosis. We conclude that, in HT mice, WPS inhalation worsened hypertension, cardiac oxidative stress, inflammation, mitochondrial dysfunction, DNA damage, apoptosis and autophagy. The latter effects were associated with a mechanism involving NF-κB activation.