This study reports process optimization studies of silica and zinc oxide-based flame-retardant (FR) coatings on cotton fabric for protective clothing and enhanced flammability properties. The experiments were designed by central composite design (CCD) using response surface methodology (RSM) to assess the synergistic protective effects of silica and zinc oxide FR coating. These prepared sols were coated on cotton fabrics by a simple dip dry cure process. The resulting FR-finished fabrics were characterized by SEM, mechanical properties, flame retardancy, and air permeability. SEM results confirmed the homogenous spreading of particles on cotton fabrics. From TGA results, it was noticed that the incorporation of silica and ZnO in the prepared nano-sols results in improved thermal stability of the FR-finished fabrics. These sol–gel-treated FR cotton fabrics showed excellent comfort properties, which shows their suitability for fire-retardant protective clothing. RSM analysis proved that the predicted values are in good agreement with the experimental values since R2 values for time to ignite, flame spread time, and air permeability were greater than 0.90. The optimized concentration of silica and ZnO in FR-finished fabrics was found to be 0.302% and 0.353%, respectively, which was further confirmed by confirmatory experiments. The optimization analysis successfully optimized the process for synergistic coating of silica and zinc oxide nanoparticles for enhanced flammability properties of FR cotton fabric for protective clothing.