Over the past decade, external pressure has been found to play an important role in modulating the structures and properties of sesqui-chalcogenides, but several key puzzles still remain to be solved. In this work, pressure-induced structural phase transitions, alloying and topological superconductivity in the ternary tetradymites Bi2Te2Se and Bi2Se2Te were investigated via in situ high-pressure angle-dispersive X-ray diffraction and resistance measurements. Both of them transform from the layered rhombohedral R3̄m structure to a 7-fold monoclinic C2/m phase, then to an 8-fold monoclinic C2/c structure, and eventually to a bcc alloy, which are quite different from previous work, but similar to the transitions in Bi2Te3. The superconductivity was found in the rhombohedral structure of Bi2Se2Te with Tc ≈ 2.2 K at 4.3 GPa, which should be related to the topological quantum transition. Furthermore, the atomic size and element electronegativity were discovered to have a significant effect on the alloying and amorphization of these compounds.