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Titanium dioxide nanoparticles (TiO2 NPs) have already been used as food additive in various products and are usually consumed with a considerable amount of sugar. Oral consumption of TiO2 NPs poses concerning health risks; however, research on the combined effect of ingested TiO2 NPs and glucose is limited. We examined young Sprague‐Dawley rats administrated TiO2 NPs orally at doses of 0, 2, 10 and 50 mg/kg body weight per day with and without 1.8 g/kg body weight glucose for 30 and 90 days. Heart rate, systolic and diastolic blood pressure, blood biochemical parameters and histopathology of cardiac tissues was assessed to quantify cardiovascular damage. The results showed that oral exposure to TiO2 NPs and high doses of glucose both could induce cardiovascular injuries. The toxic effects were dose‐, time‐ and gender‐dependent. The interaction effects between oral‐exposed TiO2 NPs and glucose existed and revealed to be antagonism in most of the biological parameters. However, toxic effects of the high‐dose glucose seemed to be more severe than TiO2 NPs and the interaction of TiO2 NPs with glucose. These results suggest that it may be more important to control the sugar intake than TiO2 NPs for protecting the health of TiO2 NP consumers.