The catalytic asymmetric construction of Csp3–Csp3 bonds remains one of the foremost challenges in organic synthesis. Metal-catalyzed cross-electrophile couplings have emerged as a powerful tool for C–C bond formation. However, these catalysts struggle to differentiate Csp3-electrophiles leading to dimerization of the starting material, and there are no general catalysts for asymmetric couplings. Here, we report a highly chemo- and enantioselective Csp3–Csp3 cross-electrophile couplings between alkyl halides and nitroalkanes catalyzed by flavin-dependent ‘ene’-reductases. Photoexcitation of the enzyme-templated charge-transfer complex between an alkyl halide and flavin cofactor enables the chemoselective reduction of alkyl halide over the thermodynamically favored nitroalkane partner. The key C–C bond-forming step occurs via the reaction of an alkyl radical with an in situ generated nitronate to form a nitro radical anion that collapses to form nitrite and an alkyl radical. An enzyme-controlled hydrogen atom transfer affords high levels of enantioselectivity. This reactivity is unknown in small molecule catalysis and highlights the potential for enzymes to use new mechanisms to address long-standing synthetic challenges.