Lanmuchang mercury-thallium mine, a typical polymetallic mine is located in southwestern Guizhou, China, is the most serious and typical area resulted from multi-metal contamination (Tl, Hg, As, and Sb). After the mercury-thallium mining, a large area of surrounding rocks such as argillaceous sandstone with high contents of Tl, Hg, As, and Sb is exposed to air. Weathering caused the argillaceous sandstone to form different weathering layers, including the grey-black external layer, the brown-yellow middle layer and the gray-white inner layer, and the external layer was enriched with higher heavy metals. However, the reason of heavy metal migration and transformation in argillaceous sandstone caused by weathering is unclear. The objective of this paper was to investigate the migration, transformation and release characteristics of Tl, Hg, As, and Sb in argillaceous sandstone during the weathering. The results indicated that weathering not only promoted an acidic oxidation environment in argillaceous sandstone, but also increased its specific surface area, pore volume and hydrophilicity, which are beneficial to the permeability of oxygen and etching liquids during the process of weathering and leaching. Meanwhile, weathering led to the transformation or decomposition of hydrophilic groups, such as -OH and -C˭O in the grey-black external layer of argillaceous sandstone, resulting in the further release of heavy metals bound to these groups. The concentration of Tl, Hg, As, and Sb in the leaching solution of argillaceous sandstone represented a positive correlation with that of Fe, Ca, Mg at different levels, indicating that Tl, Hg, As, and Sb were released with the dissolution of Fe, Ca and Mg during weathering and leaching. In summary, these results indicated that weathering caused the dissolution and migration of heavy metals in the argillaceous sandstone. Tl, Hg, As, and Sb migrated from the grey-white inner layer to the grey-black external layer and partially adsorbed by free alumina (Al_d), jarosite and Ca-bearing minerals, showing enrichment phenomena, partially released into the environment, causing environmental pollution.