<p>Selective activation of specific C–F bonds in polyfluoroarenes represents a challenge in transition metal catalysis. Here we report a photoexcited nickel-catalysed cross-electrophile coupling between polyfluoroarenes and aryl chlorides, achieving highly selective arylation at atypical C–F sites of fluoroarenes, facilitated by a synergistic lithium salt effect. A wide range of structurally diverse fluorine-containing biaryls are obtained in 33−94% yields with satisfying C–F regioselectivity. Notably, the observed regioselectivity is atypical and complements existing methodologies, such as palladium-catalysed and visible-light photoredox-catalysed defluorinative functionalization reactions. Our mechanistic studies and theoretical calculations suggest that the lithium salt could interact with both pentafluorobenzene and the Ni catalyst, effectively lowering the energy barrier and modulating the regioselectivity. The synthetic versatility of our approach is underscored by late-stage synthetic application and sequential functionalization of multiple C–F bonds, which further demonstrates its robust utility in concisely constructing partially fluorinated and biologically interesting compounds.</p><p></p>