Substituted naphthoquinones and their analogues, such as streptonigrin, are known to be involved in various important biochemical processes. It has been suggested that they are beneficial in the prevention of tumors in several major organs. Thus, synthesis of complicated naphthoquinone structures by applying the substitution reactions starting with 1,4-naphthoquinones is an endeavor that could prove to have beneficial applications for the medical field in particular. The detailed mechanisms governing these substitution processes have not been well-established. In order to disclose the mechanistic details, the substitution reactions of 2-halogeno-1,4-naphthoquinones, such as 2-chloro- and 2-bromo-1,4-naphthoquionone are studied here. We reacted 2-halogeno-1,4-naphthoquinone with alkylamines, alkyl thiols, and alkylthiolates. Two reaction mechanisms are observed dependent upon the nature of the substrate:direct substitution at the 2-halogen atom when a strong nucleophile is reacted, as opposed to addition-oxidation at the 3-hydrogen atom when reacted with thiols subjected to acidic conditions.