The presence of fine and ultra-fine gangue minerals in flotation plants can contribute to sub-optimal valuable ore recovery and incomplete water recycling from thickeners, with the performance of the latter equipment relying on adequate flocculation. In order to study the dependence of the flocculation process on the suspension-flocculant mixing conditions, a series of experiments—chosen using chemometric analysis—were carried out by varying mixing conditions, solid concentration, water salinity and flocculant dosage. To this purpose, two different tailings (both featuring coarse and fine content) were considered and a response surface methodology based on a Doehlert experimental design was used. The results suggest that the operational conditions to optimise the flocculated tailings settling rate and the suspended solids that report to a thickener overflow are not necessarily the same. This is a reasonable outcome, given that the settling rate depends on the coarse aggregates generated in the slurry, while the overflow solids content is governed both by either fine particle content (and its characteristics) or small aggregates. It is inferred that to maximise dewatering performance two stages should be involved—a separate treatment of the thickener overflow to remove fine content and thickening at optimal flocculant dosage to enhance this process.