Topological insulators (TIs) of the 124-family exhibit significant cation disorder, influencing their electronic properties. Anion substitution offers a pathway to tailor their band structure. We present a comparative study of Se-substituted GeBi${}_2$Te${}_4$ and SnBi${}_2$Te${}_4$ single crystals using TEM, XRD, momentum-resolved photoemission, DFT, and KKR methods to model disordered mixed crystals. We find that equal Te/Se substitution induces new 1222 phases due to anion site inequivalence: Te preferentially occupies outer septuple layers, while Se occupies inner layers. Cation disorder persists in Ge1222 but is suppressed in Sn1222 upon Se substitution. The band structures of Ge124 and Sn124 are similar. Upon transformation to 1222, we observe a band gap increase (from 85 to 175 meV for Sn; 180 to 195 meV for Ge), a conduction band shape change from W-like to near-parabolic, and an increase in the topological surface state’s group velocity and electron scattering—the latter attributed to enhanced impurity scattering. These findings demonstrate that Se substitution is a promising route for band engineering in TIs for potential electronic devices.