The transition towards cleaner production of primary minerals demands technologies that improve productivity while lowering their environmental impact. The present study explores a novel approach to support this transition by partially substituting a commercial froth stabilization reagent in mineral froth flotation (DowFroth200) with an amphiphilic cellulose derivative (namely, hydroxypropyl methyl cellulose) that is nontoxic, biodegradable and can be produced from sustainable sources. The performance of the cellulose-frother mixture is explored using sphalerite as case study. In the first place, the interaction between the two frother molecules was studied from the perspective of two-phase foam characteristics. The use of the polymer-surfactant (PS) mixture studied reported an increased foam stability and small bubble sizes, attributed to a combination of liquid film drainage prevention and steric effects of cellulose macromolecules. As a result, when used as frothers in the flotation of sphalerite, the PS-mixture exhibited a robust behavior resulting in advantages such as: i) improved separation efficiencies; ii) consistent recovery values, even under highly alkaline pH, iii) maintaining high recoveries when the collector dosage was reduced down to 25% of typical values used in the industry; and iv) faster flotation kinetics. The results obtained aim to demonstrate that properly designed green chemical systems can have a positive impact in the mining sector.