Chemotherapy tends to stop the growth and eliminate cancer cells even at distant sites. Most of them lead to adverse side effects and induce changes in normal tissues. The aim of the present study was to evaluate of apoptotic changes induced by 5-fluorouracil on the lingual mucosa and salivary glands of male albino rats through clinical, histological, immunohistochemical and histomorphometric assessments. Twenty male albino rats were divided equally into two groups. Control group did not receive any type of treatment and study group received intraperitoneal injection of 5-FU (150 mg/kg) for 7 days. On the 14th day, the tongue and submandibular salivary gland specimens were dissected and processed. The study group showed histopathological changes as atrophy of the lingual papillae which confirmed statistically through histomorphometric analysis. The submandibular glands showed marked degeneration in the duct system and acini. The assessment of apoptosis was confirmed by immunohistochemical findings, there was highly statistically significant increase in the expression pattern of Bax and Caspase-3 with significant decrease in PCNA level in comparison to the control group. So, 5-FU caused deleterious histopathological and immunohistochemical alterations of the submandibular salivary glands and tongue mucosa.