In this study, two polymers, polyacrylamide and carboxymethyl cellulose, were used together with magnesium oxide nanoparticles to reduce the drag of horizontal pipelines made of galvanized, copper, and 5-layer materials. In each pipeline, three parameters affecting the process, magnesium oxide nanoparticle concentration (0 to 160 mg/L), polymer concentration (0 to 64 mg/L), and Reynolds number (6400 to 25600), were investigated by the response surface method using the Design of Experiment-13 software. Then, a comparison was made between the drag reduction rates of the two polymers, polyacrylamide and carboxymethyl cellulose, in each pipeline. The drag reduction rate was predicted using the obtained model. By increasing the value of all three parameters under investigation, namely Reynolds number, polymer concentration, and nanoparticle concentration, the drag reduction rate increased significantly. Among these factors, Reynolds number had the greatest effect on drag reduction, followed by polymer and nanoparticle concentration, respectively. The results of the study in all three pipelines showed that the drag reduction using carboxymethyl cellulose polymer was less than the drag reduction using polyacrylamide polymer. Therefore, polyacrylamide showed better performance in drag reduction in three pipelines: galvanized, 5-layer, and copper. The results showed that in galvanized pipe, polyacrylamide was about 17% more effective than carboxymethyl cellulose in drag reduction, in five-layer pipe about 16% more effective than carboxymethyl cellulose in drag reduction, and in copper pipe about 19%.