Chrysanthemum cinerariifolium (Trev.) Vis. leaves have potential anticancer activity and are expected to inhibit oral squamous cell carcinoma (OSCC) progression. The present study aimed to determine the effect of ethanol extract of C. cinerariifolium leaves on the number of macrophages, IL-17 levels, and degree of keratinization in the OSCC rat model. Thirty male Sprague Dawley rats (weighing 80-160g, 2-3 months old) were randomly divided into five groups (n=6): (1) negative control (healthy rat, untreated); (2) positive control (OSCC rat); (3-5) dose 1, 2 and 3 (OSCC rat received 50, 100 and 200mg/kg BW of C. cinerariifolium leaves, respectively). The tongues of the rats were prepared for Hematoxylin-Eosin (HE) staining and immunohistochemistry. The number of macrophages was determined under a light microscope with 400x magnification. The level of IL-17 was examined using an ELISA assay. The degree of keratinization was calculated using the ImageJ software. All doses of C. cinerariifolium leaves extract could reduce the number of macrophages in OSCC rats. The levels of IL-17 in OSCC rats were decreased after being treated with 100 and 200mg/kg BW of C. cinerariifolium leaves extract. The high dose of C. cinerariifolium leaves extract (200mg/kg BW) reduced the degree of keratinization in the OSCC rat model. The study revealed that C. cinerariifolium leaves extract could inhibit the progression of OSCC by reducing macrophage, IL-17 and keratinization.