This study demonstrates the effectiveness of synthetic nicotinamide cofactors as cost-effective alternatives to NADPH in imine reductase (IRED) catalysis. The synthetic cofactors maintained catalytic activity and stereoselectivity, achieving high conversion rates. Molecular docking studies revealed key structural interactions influencing performance. Combining a glucose dehydrogenase (GDH) recycling system further enhanced the stability and efficiency. These findings highlight the potential of synthetic cofactors to reduce costs and improve the feasibility of IRED-catalyzed processes for industrial applications.