Feline chronic gingivostomatitis (FCGS) is a painful inflammatory disease of the oral cavity in which partial-mouth or full-mouth extraction (PME or FME) is considered the standard treatment. However, longitudinal information regarding histopathologic and local immunologic changes after surgery remains limited. The aim of this pilot prospective study was to assess the clinical, hematologic, biochemical, histopathologic, and immunologic evolution of cats with FCGS following PME. Five cats diagnosed with FCGS were enrolled and followed longitudinally. Clinical response was assessed in the five cats using the Stomatitis Disease Activity Index (SDAI), together with hematologic, biochemical, and retroviral testing. Biopsies of the caudal oral mucosa were collected from three cats before surgery and 30 days after surgery for histopathologic evaluation using a previously described inflammatory scoring system. Immunolabeling of CD20, FoxP3, and IL-17 was quantified by digital image analysis. Clinical scores improved after PME, although the magnitude of the response varied among individuals. Persistent non-regenerative anemia and marked monocytosis were observed in cats positive for feline leukemia virus and/or feline immunodeficiency virus. Hyperglobulinemia was the most common biochemical abnormality. Histopathologic examination revealed moderate-to-marked lymphoplasmacytic inflammation associated with epithelial hyperplasia, edema, and, in the most severe cases, spongiosis and necrosis. Sequential biopsies demonstrated reductions in histologic inflammatory scores in two of three cats. CD20 immunolabeling decreased post-PME, whereas FoxP3 and IL-17 expression showed marked interindividual variability. This pilot prospective study provides preliminary observations on tissue changes in the early stages following PME.