We investigate chemical control of the electronic, optical, and topological properties of two-dimensional Si2X2Te2 (X = B, Al, Ga, and In) monolayers using first-principles calculations. All compounds are dynamically stable semiconductors, with their vibrational and electronic properties evolving systematically upon group-III substitution. Hybrid-functional calculations including spin–orbit coupling reveal predominantly p-orbital band edges and increasingly pronounced relativistic effects from B to In. Most notably, the calculated Z₂ invariant identifies Si2In2Te2 as a candidate quantum spin Hall insulator, while the B-, Al-, and Ga-based monolayers remain topologically trivial. Bethe–Salpeter calculations further show that electron–hole interactions redistribute oscillator strength near the absorption onset while preserving a weak in-plane optical anisotropy. Our results establish group-III substitution as a simple chemical route to tune the electronic structure and drive a transition from trivial to nontrivial topology in Si2X2Te2 monolayers.