A series of new amphoteric block bipolymers were prepared by the functionalization of PEO-PPO-PEO block bipolymers with a terminal tertiary amine and subsequently, with acrylic acid derivatives by means of Michael reaction. In addition to the chemical process mentioned earlier, the amphoteric block bipolymers were characterized by 1D and 2D nuclear magnetic resonance, size exclusion chromatography, and thermo-gravimetric analysis. Afterward, the dehydrating capacity of the new demulsifiers was evaluated in three heavy crude oils and one light crude oil. Finally, a quantitative structure-activity relationship analysis was deployed using quantum parameters of the amphoteric bipolymers and physicochemical parameters of the crude oils. For the training set and the external validation, a set of 24 water removal efficiency (WRE) values were considered. In the scope of the training set, six equations, V1-V6, fulfilled the restriction of Q(2) value > 0.60. Regarding the external validation, the r(m)(2) criterion >0.50 was considered to be the main restriction to validate the eqs V1-V6. In this case, the eq V1 showed the highest r(m)(2) value of 0.72, which was therefore singled out as the best to calculate the WRE value for the amphoteric block bipolymers. Conclusively, the theoretical and experimental results demonstrated that a single amphoteric block bipolymer, with an adequate functional group, can evidently act as the demulsifier agent for great variety of crude oils in a more efficient manner than a conventional combination of several commercial polyethers.