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[Display omitted] • Co-overexpression of GLK1 and PGM1 significantly promoted cordycepin accumulation. • Molasses, DHP, and waste yeast as alternate enhanced cordycepin production. • High C/N molar ratio and weak acidic were more conducive to producing cordycepin. • The cordycepin productivity in the optimized medium was increased by 28.81%. • Using agro-industrial residues can reduce the cost of cordycepin production. Cordycepin, a nucleoside compound with a variety of biological activities, has been extensively applied in the nutraceutical and pharmaceutical industries. The advancement of microbial cell factories using agro-industrial residues provides a sustainable pathway for cordycepin biosynthesis. Herein, the cordycepin production was enhanced by the modification of glycolysis and pentose phosphate pathway in engineered Yarrowia lipolytica. Then, cordycepin production based on economical and renewable substrates (sugarcane molasses, waste spent yeast, and diammonium hydrogen phosphate) was analyzed. Furthermore, the effects of C/N molar ratio and initial pH on cordycepin production were evaluated. Results indicated that the maximum cordycepin productivity of 656.27 mg/L/d (72 h) and cordycepin titer was 2286.04 mg/L (120 h) by engineered Y. lipolytica in the optimized medium, respectively. The cordycepin productivity in the optimized medium was increased by 28.81% compared with the original medium. This research establishes a promising way for efficient cordycepin production from agro-industrial residues. [ABSTRACT FROM AUTHOR]