Over the past decade, colchicine has re-emerged as a promising therapeutic candidate for atherosclerotic cardiovascular disease. Here we review evidence from large randomized controlled trials together with advances in mechanistic research that have clarified how colchicine modulates vascular inflammation and plaque stability. Canonically, colchicine disrupts microtubule dynamics and suppresses NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation. Beyond these actions, it limits oxidative stress, modulates cytoskeletal cross-talk, attenuates cholesterol crystal formation and reprograms inflammatory and metabolic proteomic networks. Colchicine influences multiple vascular and immune cell types, including neutrophils, monocytes, macrophages, endothelial cells, smooth muscle cells and platelets, collectively reducing vascular inflammation and promoting plaque stability. Notably, while colchicine has demonstrated benefit in coronary artery disease, several recent trials in cerebrovascular disease have reported neutral outcomes, suggesting disease-specific inflammatory mechanisms and therapeutic responsiveness. Integrating mechanistic insights with clinical evidence will be critical to optimize colchicine use and advance precision anti-inflammatory strategies in atherosclerotic cardiovascular disease.