Currently, most coal processing plants use a single pharmaceutical system with large dosage and poor sedimentation effect, resulting in poor subsequent dehydration effect. In this study, poly dimethyl diallyl ammonium chloride (PDMDAAC) as coagulant, and polyacrylamide (PAM) as flocculant, were used for synergistic enhancement of the coal slurry water sedimentation and dehydration process. The best pharmaceutical system was determined by integrating the evaluation indexes in the sedimentation and dehydration process. The mechanism of synergistic enhancement of coal slurry water sedimentation and dehydration process using PDMDAAC/PAM was revealed by analyzing zeta potential, SEM, XPS and FTIR spectroscopy results. Moreover, the Box–Behnken response surface methodology was used to determine the order of significance of coagulant dosage (Cc), flocculant dosage (Cm), and coal slurry water concentration (Cs) on the combined sedimentation and dehydration indexes, and Cm > Cs > Cc. Further, the correlation models between the combined sedimentation and dehydration indexes and each factor were established, the pharmaceutical system was further optimized, and model accuracy was verified. The optimal dosage of PDMDAAC10040 was 2.96 mg/L, and that of PAM2610 was 2.31 mg/L. Then, the industrial trials were conducted at the Tara Trench coal processing plant. Interestingly, after replacing the chemical regime, the efficiency of the thickener and filter press has been significantly improved, resulting in a 33.33% reduction in cost. This research can provide significant theoretical guidance and technical support for industrial applications.