Disclosed is a method of preparing a glycol mono-tertiary-butyl ether compound using a C4 hydrocarbon mixture containing isobutene and a glycol compound as reactants, in which a glycol di-tertiary-butyl ether compound as a byproduct is decomposed into isobutene and a glycol compound and the obtained isobutene and glycol compound are recycled as reactants, whereby product yield per unit raw material may be maximized. The method includes a catalytic reaction step for preparing a glycol mono-tertiary-butyl ether compound and a glycol di-tertiary-butyl ether compound as a byproduct by reaction between a glycol compound and a C4 hydrocarbon mixture containing isobutene in the presence of an acidic catalyst, a byproduct extraction step for separating the glycol mono-tertiary-butyl ether compound and the glycol di-tertiary-butyl ether compound, prepared through the catalytic reaction step, using a hydrophilic extractant and a lipophilic extractant, and a byproduct decomposition and recycling step for decomposing the separated glycol di-tertiary-butyl ether compound into a glycol compound and isobutene and recycling the decomposed glycol compound and isobutene as the reactants to the catalytic reaction step.