Chemical, biological, radiological and nuclear (CBRN) accidents or attacks typically disseminate contaminants inside and outside buildings and structures whose surfaces have to be decontaminated. This paper describes an innovative colloidal gel formulation and its effects against CBR threat agents and also against prion contaminations. The gel’s rheological properties ensure it remains attached even to vertical surfaces. The gel then dries with the contaminants trapped inside, leaving behind non-dusting solid residues that are easy to recover by brushing or vacuum cleaning. The results obtained here on different formulations show that decontamination proceeds in two steps. Contaminants are first solubilized or absorbed into the gel thanks to the efficient wetting of the surface by the gel. Chemical and biological agents are then neutralized by the NaOH and hypochlorite ions in the gel. This article demonstrates the efficiency of this CBR gel against Bacillus anthracis, the chemical agents sulfur mustard, VX, and soman, 137Cs, and prion proteins.