Purpose <p>This study investigated foliar-applied silicon dioxide (SiO₂​), alone and with calcium (Ca), as a sustainable strategy to enhance lettuce quality and performance, using a genetically diverse panel of accessions for broad applicability.</p> Methods <p>We conducted multi-year outdoor pot and field experiments to assess the effects of a range of SiO₂​ and Ca concentrations and a promising subset of treatments, respectively. We evaluated key horticultural traits, resistance to diseases, pests, and physiological disorders, as well as post-harvest quality and plant mineral composition.</p> Results <p>The treatments provided significant benefits for several quality-related traits. A combination of 3.66&#xa0;mM SiO₂ and 2.50&#xa0;mM Ca significantly improved plant biomass, leaf thickness, and anthocyanin concentration in pot experiments. In field trials, 3.66&#xa0;mM SiO₂​ application delayed bolting, reduced downy mildew severity, and increased leaf thickness, chlorophyll, and anthocyanin content. Notably, the combined SiO₂ and Ca spray significantly reduced post-harvest deterioration in both pot and field experiments, demonstrating a synergistic interaction. Analysis of mineral elements revealed that the treatments modified the uptake and correlations among several elements in the plant tissue.</p> Conclusion <p>Foliar SiO₂​ and Ca applications, particularly in combination, represent an effective approach for enhancing key lettuce quality parameters. While no significant yield gains were observed in field trials, the improvements in post-harvest quality, disease resistance, delayed bolting, and plant composition are clear evidence that this strategy can reduce crop losses and improve overall product quality.</p>