ABSTRACT: Intermittent fasting (IF) reduces the inflammatory symptoms of Rheumatoid Arthritis (RA); however, its anti-inflammatory underlying molecular mechanisms are unknown. Aim: To investigate the effect of IF on joint inflammatory molecular mechanisms in collagen-induced arthritis (CIA) through DNA microarray and clinical and histopathological evaluations. Methods: CIA was induced in sixteen male DBA/1 mice divided into two groups, one received every other day IF for four weeks. The clinical, histological, and transcriptomic analyses, through DNA microarray, were done to evaluate the effect of IF on joint inflammation and remodeling. Results: CIA mice with IF show lower arthritis incidence and severity. IF also decreased the histological inflammation and joint damage. DNA microarrays dataset revealed 364 overexpressed and 543 subexpressed genes. The highest over- and subexpressed genes were the Ereg and MUPs, respectively. Retinol biosynthesis and the macrophage alternative activation pathways were associated with a positive z-score. Pathways with negative z-scores were related to the inflammatory process, including systemic lupus erythematosus in B cells and osteoarthritis, in which the RA-related genes Cd72, Cd79a, Ifna, Il33, and Bglap2 were found to be decreased. The bioinformatic algorithm identified four central possible regulators: CEBPA, FOXO1, HIF1A, PPARG, and PPARA. In the analysis of diseases and biofunctions, molecular transport, small molecule biochemistry, and lipid and carbohydrate metabolism tended to increase; conversely, organismal injury and abnormalities, inflammatory response, metabolic diseases, cancer, and endocrine, reproductive, gastrointestinal, skeletal, and muscular system disorders, were decreased by IF