Aim: To determine the dynamics of histological changes in the lobules of rat submandibular salivary glands under normal conditions and following the combined administration of the food additives monosodium glutamate, sodium nitrite, and Ponceau 4R. Materials and Methods: Rats of the experimental group received sodium nitrite at a dose of 0.6 mg/kg, monosodium glutamate at a dose of 20 mg/kg, and Ponceau 4R at a dose of 5 mg/kg dissolved in 0.5 mL of distilled water and administered orally once daily. The animals were euthanized after 1, 4, 12, and 16 weeks of the experiment. Histological examination of the submandibular salivary glands was performed. Results: Prolonged administration of the combination of food additives, including monosodium glutamate, sodium nitrite, and Ponceau 4R, resulted in stage-dependent morphological alterations. At the early stages, vascular-stromal disturbances and functional stress of the glandular epithelium predominated, accompanied by the development of persistent interstitial edema, hydropic degeneration, and ductal dysfunction. At later stages of the experiment, compensatory activation of a portion of glandular cells was observed in combination with dystrophic changes and microcirculatory imbalance. By the end of the study, these alterations manifested as chronic dystrophic remodeling, mucinous transformation of the secretory end pieces, desquamation of the ductal epithelium, and disruption of the structural integrity of the ductal system. Conclusions: Administration of the combination of food additives leads to destructive and dystrophic changes in the structural components of the submandibular salivary glands and is accompanied by remodeling of the extracellular matrix components.