A novel process for the synthesis of tetrabenazine (1) and deutetrabenazine (2), two well-known drugs used for the treatment of chorea associated with Huntington’s disease, has been developed. All of the reaction parameters were optimized through a series of reactions and by using Design of Experiment techniques. The newly developed methods are industrially scalable and employ cheap, commercially available raw materials and hence are highly efficient. The added advantage is that the developed processes evade the use of genotoxic alkylating agents and therefore could be considered as safe and viable alternatives to the existing methods.