Here, the systems metabolic engineering of L-lysine-overproducing Corynebacterium glutamicum is described to create a highly efficient microorganism producer. The key chromosomal mutations associated with L-lysine synthesis were identified based on whole-genome sequencing. The carbon flux was subsequently redirected into the L-lysine synthesis pathway and increased the availability of energy and product transport systems required for L-lysine synthesis. In addition, a promoter library sensitive to intracellular L-lysine concentration was constructed and applied to regulate the NADPH pool dynamically. In the fed-batch fermentation experiment, the L-lysine titer of the final engineered strain was 223.4 ± 6.5 g/L. This study is the first to improve L-lysine production by enhancing ATP supply and NADPH self-regulation to improve the intracellular environment.