The efficient treatment of domestic wastewater is associated with good operational practices in wastewater treatment plants (WWTP) and the proper design of each treatment unit, which ensures the correct hydraulic performance of each WWTP. For this reason, the objective of this article was to study the design of the multiple influent distribution systems of a high-rate primary sedimentary, a UASB (Upflow Anaerobic Sludge Blanket) reactor, and an up-flow anaerobic filter (FAFA) in the WWTPs of the municipalities of San Carlos and San Roque, and in the township of Santiago, respectively, located in Antioquia-Colombia. For this purpose, the methodology proposed by Hudson in 1981 was used to evaluate the performance of the current design and, subsequently, a pre-dimensioning was carried out to distribute the flow uniformly, to have velocities within the ranges recommended by the literature, and to obtain the total head loss generated by the distribution manifold in each treatment unit evaluated. It was found that the existing design is not efficient and that the new pre-dimensioning ensures homogeneous flow distribution and provides velocities that contribute positively to the treatment process. The study concludes that the smaller the number of orifices and the larger the pipe diameter, the more uniform the flow distribution, and that the total head loss depends on both the velocity head and the head loss coefficient. The diameter of the orifice was the predominant parameter to control the inlet velocity of the treatment units.