Apoptotic signals, inflammatory mediators, and oxidative stress are up-regulated in ulcerative colitis (UC), which increases the risk of colon cancer. In UC, oils are being investigated as protective agents. Therefore, the current study is concerned with comparing the potential effectiveness of grape seed oil (GSO) and flaxseed oil (FSO) in modulating the risk factors associated with UC condition induced by acetic acid (AA). Twenty-four adult male rats were divided into four groups/6 rats each; control group received distilled water, UC group intrarectal treated with a single dose of 4% AA; GSO and FSO groups administrated 5 mL/kg body weight of grape (Vitis vinifera L.) seed oil or flaxseed (Linum usitatissimum L.) oil, respectively for three weeks before the induction of the UC. Protective effects were determined by measuring tissue Hemoxegenase 1, Monocyte chemoattractant protein 1, Myeloperoxidase, Tumor necrosis factor alpha and Interleukin-10 as well as serum oxidative markers, such as malondialdehyde, and total antioxidant capacity. In addition, macroscopic, histopathological and immunohistochemical examinations of colon tissues. The findings showed that inducing UC in rats activated the pro-inflammatory, apoptotic, and lipid peroxidation pathways. However, the exacerbated effects of ulceration on the colonic mucosa could be effectively reversed by GSO and FSO. Surprisingly, FSO was more efficient to exert its colo-protective effect, as confirmed by histopathological/immunohistochemical changes. Therefore, FSO may be a promising therapy for treating UC.