This study investigated whether N-acetylcysteine (NAC) supplementation could reverse the negative effects of a high-fat diet (HFD) on mitochondrial function, apoptosis, and oxidative stress in the salivary glands of hyperglycemic rats. While NAC increased the activity of some mitochondrial complexes and decreased certain inflammatory markers in parotid glands, it did not significantly improve other parameters in either parotid or submandibular glands. The findings suggest that NAC offers limited protection against free radical damage, apoptosis, and inflammation in the salivary gland mitochondria of HFD rats.