We investigate the structural, electronic, and phonon transport properties of GaSe0.5Te0.5 and InSe0.5Te0.5 systems in centrosymmetric (CS) and non-centrosymmetric (NCS) configurations using first-principles calculations combined with Boltzmann transport theory. Structural optimization and stability analysis confirm the feasibility of both configurations. Our results show that crystal symmetry plays a decisive role in governing charge and phonon transport. The centrosymmetric phases exhibit higher carrier mobility, reaching 5407 cm²/Vs for CS-GaSe0.5Te0.5 and 1872 cm²/Vs for CSInSe0.5Te0.5, due to reduced carrier–phonon scattering and more symmetric electronic band dispersion. Interestingly, while both Ga and In-based systems are expected to show superior electrical conductivity due to “conductive network” overlap, the additional antibonding character from In–Te bonds in Insystem may further suppress phonon transport, resulting in reduced lattice thermal conductivity. Additionally, inversion-symmetry breaking in the NCS structures enhances lattice anharmonicity, strengthens phonon scattering, and reduces phonon group velocities, leading to a strong suppression of in-plane lattice thermal conductivity. Moreover, the absence of inversion symmetry in the NCSconfiguration induces Rashba-type spin splitting, which modifies the electronic band structure and enhances the Seebeck coefficient. As a result of this symmetry-driven interplay between electronic and phononic transport, NCS-InSe0.5Te0.5 exhibits the best thermoelectric performance, achieving a maximum ZT of ~2.7 at 600 K. These results highlight symmetry engineering as an effective strategy to optimize thermoelectric efficiency in layered chalcogenide systems.