The selective activation of inert C–F bonds is one of the most challenging topics in modern organic chemistry. Trifluoromethylketones represent a class of versatile building blocks that are inexpensive and readily available polyfluorinated starting materials. The functionalization of C–F bond in trifluoromethylketones has recently been achieved using difluoroenolates, difluorinated acyl anions or radicals for the synthesis of difluoromethylene compounds. This strategy has also been successfully applied to their derivatives, such as trifluoromethylated esters, amides, diazo compounds and N-sulfonylhydrazones, which would be of significant value for the synthesis of partially fluorinated intermediates. In this review, we mainly focus on the recent advances, challenges and perspectives of trifluoromethylated carbonyl compounds and their derivatives via C–F bond activation, along with mechanistic insight.