We describe a photoenzymatic hydroalkylation reaction that enables the efficient and stereocontrolled synthesis of aryl glutarimide precursors—chemically and configurationally robust entry points to bioactive agents for targeted protein degradation. Screening of flavin-dependent “ene”-reductases identified GluER HA_rac, a G. oxydans variant, as an efficient and substrate-tolerant catalyst, granting access to >30 (hetero)aryl glutarimide precursors. A directed evolution campaign then furnished a hexamutant, GluER HA_ent, that delivers the products in up to 93:7 enantiomeric ratio. Mechanistic experiments revealed a pathway that departs from the hydrogen atom transfer mechanism previously established for related systems, proceeding instead via radical–polar crossover followed by enantioselective proton transfer from an active-site tyrosine residue. Collectively, these studies establish a biocatalytic platform for advancing the synthesis and diversification of glutarimide-containing degraders.