Electrospun bio-based nanofibers have emerged as promising materials for air filtration, although their optimization remains strongly dependent on both composition and operating conditions. In this study, the velocity-driven effects of zein (ZN) and cellulose acetate (CA) addition on the nanoaerosol filtration performance of electrospun poly(vinyl alcohol)/chitosan (PVA/CS) nanofibers were investigated using response surface methodology (RSM). Nanofibrous mats were produced from a previously established PVA/CS electrospinning system, and thirteen formulations were defined through a central composite design varying ZN and CA contents. Filtration performance was evaluated with NaCl nanoparticles in the 7–250 nm range at air filtration velocities of 3.0, 4.5, and 6.0 L·min⁻¹, while pressure drop and quality factor were also determined. The addition of 5 wt% ZN and CA caused only minor changes in fiber morphology, with all formulations remaining within the 150–230 nm diameter range. In contrast, filtration behavior was markedly influenced by velocity. Collection efficiencies generally remained between 95 and 99%, with MR05 showing the highest efficiency at 3.0 L·min⁻¹, MR06 at 4.5 and 6.0 L·min⁻¹, and MR12 exhibiting the lowest pressure drop across all velocities. All RSM models were statistically significant, with pressure drop responses showing ...