As a powerful platform in drug discovery, the DNA-encoded chemical library technique enables the generation of numerous chemical members with high structural diversity. Epoxides widely exist in a variety of approved drugs and clinical candidates, eliciting multiple pharmaceutical activities. Herein, we report a non-oxidative DNA-compatible synthesis of di-/trisubstituted α,β-epoxyketones by implementing aldehydes and α-chlorinated ketones as abundant building blocks. This methodology was demonstrated to cover a broad substrate scope with medium-to-excellent conversions. Further structural diversification and transformation were also successfully explored to fully leverage α,β-epoxyketone moiety.