In this work, polyacrylamide functionalized chitosan polymers (CS-PAMs) of different structural properties were synthesized and investigated as selective depressants of pyrite (FeS2) in the flotation process of galena (PbS) and chalcopyrite (CuFeS2) from a complex sulfide ore. Response surface methodology (RSM) with a Box-Behnken design was applied for modeling and optimization of the flotation process in the presence of CS-PAMs wherein process parameters pertained to CS-PAM's structural characteristics were varied. These parameters included the degree of deacetylation of chitosan backbone (DD), weight ratio of chitosan:acrylamide, and CS-PAM's dosage. Quadratic equations were developed for the prediction of the grades and the recoveries of iron, lead, and copper in the flotation concentrates. The developed RSM models showed good prediction performance for iron and lead but performed poorer for copper. Optimization studies indicated that the selective separation of pyrite from galena and chalcopyrite was optimal when using 85 g/t of CS-PAM synthesized from chitosan with DD = 95% at 1:4.5 weight ratio of chitosan:acrylamide. At these optimum conditions, the minimum grade and recovery of iron in the flotation concentrates were 3.06% and 15.33% respectively, compared to 9.84% grade and 83.41% recovery of lead and 1.70% grade and 63.37% recovery of copper.