Background: Pomegranate seed oil (PSO) and avocado seed oil (ASO) are natural polyphenols with established anti-inflammatory activity. Purpose: This study aimed to investigate the molecular mechanisms underlying the therapeutic efficacy of PSO and ASO in experimental ulcerative colitis (UC) with reference to sulfasalazine (SLZ). Methods: Eighty male albino rats were divided equally into 8 groups; Normal, PSO, ASO, SLZ, UC-control, (UC & thorn; PSO), (UC & thorn; ASO) and (UC & thorn; SLZ) groups. Colitis was induced by intra-rectal injection of acetic acid. PSO (0.5ml/200g), ASO (1ml/250g) and SLZ (100 mg/kg) were administered orally once/day for 14 days, 24h after colitis induction. Colitis was evaluated by measuring disease activity index (DAI), colon weight/ length ratio and histologic inflammatory score. Vascular endothelial growth factor receptor -2 (VEGFR-2), colonic macrophage migration inhibitory factor (MIF), and malondialdehyde (MDA) were determined. Colonic gene expression of TNF- a, VEGF and heme oxygenase-1 (HO -1) were also estimated. Results: PSO and ASO treatments to UC rats significantly reduced DAI, weight/length ratio, VEGFR-2, and colon histologic inflammatory score versus UC-controls. ASO significantly suppressed MIF levels and TNF- a expression greater than PSO. However, PSO was more significant than ASO in reducing MDA levels and up -regulating HO -1 expression. Both oils significantly down -regulated VEGF expression. The obtained biochemical and histological changes induced by UC were nearly corrected by SLZ. Conclusion: The proved beneficial effect of PSO and ASO as anti-inflammatory, anti-angiogenic, and antioxidant in UC rats could be mediated by suppression of TNF- a, VEGF, and MIF and up -regulation of HO -1. (c) 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.