Several environmental problems have been reported when synthetic organic and inorganic flocculants are used to treat fluid fine tailings (FFT), especially phyllosilicate clay minerals, generated in the mining plants. These hazardous issues have increased the importance of using natural flocculants from renewable sources (biopolymers). This investigation has explored the impact of proteins (protamine and lysozyme) and polysaccharides (chitosan, pectin, lignin, and alginic acid) as natural flocculants and compared their results in the same conditions by using Polyacrylamide (PAM) as a traditional organic polymer. Ultrafine kaolinite and serpentine particles (−10 μm) were chosen as the challenging gangue minerals for chalcopyrite copper ore (CuFeS2) and pentlandite nickel ore ((Fe, Ni)9S8)), respectively. Capillary suction timer (CST) and filtration tests were considered for comparative assessments. Assessments indicated that PAM in shear rate ~ 20 (1/s) has a viscosity ~90 times higher than the examined biopolymers. This high viscosity limited PAM distribution as a flocculant through the suspensions. Results highlighted that PAM had the highest flocculation activity in low dosages (0.05 and 0.1 wt%) while in dosages above 0.25 wt%, cationic biopolymers; protamine, and lysozyme for kaolinite and anionic pectin for serpentine showed a higher performance than the other polymers. The addition of Ca2+ could increase the dewatering of the clay minerals and promote the flocculation strength of the biopolymers. Generally, results indicated that the flocculation function of protamine and lysozyme (cationic proteins) at the optimum dosage (0.5 wt%) was higher than other tested biopolymers, while pectin (an anionic polysaccharide) improved the dewatering of serpentine particles. Outcomes of this study proved that commercially available bioflocculants have a significant potential to use in the treatment of FFTs and decrease environmental problems that occur by using inorganic and organic flocculants.