Chronic inflammatory bowel diseases (IBDs), particularly colitis, remain a major health burden due to the limitations of current therapies, including adverse effects and diminishing efficacy. Artemisia herba-alba (A. herba-alba), a medicinal plant traditionally used in North Africa and the Middle East, holds promise as a natural anti-inflammatory agent. However, the efficacy of A. herba-alba against chronic colitis is underexplored. The aim of this study was to undertake a comprehensive investigation combining phytochemical analysis, ADMET predictions, toxicity assessment, and in vivo evaluation. High-performance liquid chromatography (HPLC) detected 5 major bioactive compounds: nicotinic acid, gallic acid, rutin, catechin, and caffeic acid. ADMET profiling using SwissADME, ADMET-AI, and ProTox-II indicated favorable pharmacokinetic properties and low predicted toxicity (LD(5)(0) >2000 mg/kg). A 30-day subchronic toxicity study in mice treated with up to 1000 mg/kg of extract confirmed its safety, with no mortality, behavioral changes, or organ abnormalities. Therapeutic efficacy was evaluated in a carrageenan-induced subchronic colitis murine model. Oral administration of A. herba-alba extract (500 mg/kg) significantly alleviated colitis, preserving colon length and improving mucosal architecture. Histological analysis revealed reduced crypt damage and inflammatory cell infiltration. Taken together, these results confirm the favorable safety profile and beneficial therapeutic potential of A. herba-alba, supporting its development as a multi-targeted, natural treatment for chronic colitis.