Objective To explore the effect of colchicine on atherosclerotic unstable plaque formation in high fat diet-fed New Zealand rabbits and the underlying mechanism. Methods A total of 32 male New Zealand rabbits at 3 months of age were randomly assigned into a control group (n= 8), model group (n= 8), colchicine group (n= 8), and pitavastatin group (n= 8). Serum blood lipids, high sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6) were measured at 8 and 12 weeks postoperatively. Rabbits were sacrificed at 12 weeks postoperatively, and blood vessels were collected to prepare paraffin-embedded sections, followed by observation of blood vessel morphology by HE staining. AMP-activated protein kinase ( AMPK), sirtuin 1 ( SIRT1), and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) mRNA levels in unstable plaques were measured by qRT-PCR. p-AMPK, SIRT1, and PGC-1α protein levels were measured by Western Blot and immunohistochemistry. Malondialdehyde ( MDA) and superoxide dismutase (SOD) activities in unstable plaques were determined by chromogenic reaction. Intravenous ultrasound was performed to visualize plaque formation. Results Relative levels of blood lipids and inflammatory indicators in model, colchicine, and pitavastatin groups at 12 weeks postoperatively were significantly higher than those in the control group (P< 0. 05). Triglycerides, low-density lipoprotein-cholesterol, hsCRP, and IL-6 levels in the colchicine group were significantly lower than those in the model group (P< 0. 05). Neointimal hyperplasia was observed in model, colchicine, and pitavastatin groups, and typical atherosclerotic plaque formation was seen in the model group. Upregulation of p-AMPK, SIRT1, and PGC-1α was detected in rabbit plaques and hyperplastic intima, which was most pronounced in the colchicine group (P< 0. 05). Intravenous ultrasound scans showed moderate-severe lumen stenosis, plaque rupture, and subintimal hemorrhage in the model group. Moderate lumen stenosis was seen in colchicine and pitavastatin groups without plaque rupture. Decreased MDA content and increased SOD activity were found in the colchicine group compared with model and pitavastatin groups. Conclusions Colchicine delays atherosclerotic plaque formation in high fat diet-fed New Zealand rabbits by reducing lipid accumulation in plaques, AMPK-induced activation of deacetylase, upregulation of SIRT1 and PGC-1α, and inhibition of oxidative stress and inflammatory responses by enhancing the release threshold of proinflammatory factors in plaques.