The state of dispersion and the interactions between a polymer and a filler in a nanocomposite crucially define its properties and performance. The affinity of polylactide (PLA) with vegetable and animal proteins (casein, gelatin, soy protein isolate, and hydrolysate) is investigated and their role as eco-friendly dispersants and compatibilizers of cellulose nanofibrils (CNF) is elucidated. The affinity of the proteins with PLA is determined by using sensograms acquired by electroacoustic (quartz crystal microgravimetry) and optical (surface plasmon resonance) techniques. The surface energy of PLA increases upon protein adsorption while the opposite effect is observed for CNF, under identical experimental conditions. A significant improvement in the thermodynamic work of adhesion for PLA/CNF systems is predicted by application of the denatured proteins at low concentrations (∼20% and ∼15% enhancement with soy protein and casein at pH 3 and pH 8, respectively). We offer a robust method to screen denatured proteins and to tailor the wettability and material compatibility in the synthesis of bionanocomposites based on CNF and PLA.