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In indoor vertical farms, energy consumption represents a bottleneck for both a system’s affordability and environmental footprint. Although switching frequency (<i>sf</i>) represents a crucial factor in determining the efficacy of light emitting diodes (LED) lighting systems in converting electricity into light, the impact of <i>sf</i> is still underexplored. The aim of this work was to investigate the effect of LEDs <i>sf</i> on the productive and qualitative responses of lettuce (<i>Lactuca sativa</i> L.), also considering the resource use efficiency. Plants were grown for 14 days under red and blue LEDs (215 μmol m⁻² s⁻¹ and 16/8 h light/dark, with a red:blue ratio of 3) characterized by two different <i>sf</i> for the blue diode, namely high <i>sf</i> (850 kHz) and low <i>sf</i> (293 kHz). A fluorescent light (same light intensity and photoperiod) was included. LED <i>sf</i> did not alter plant morphological parameters, including fresh or dry biomass, leaf number, leaf area, or water use efficiency. A low <i>sf</i> increased the energy use efficiency (EUE) by 40% as compared to high <i>sf</i>. The latter enhanced the leaf antioxidant capacity, as a consequence of increased concentrations of caftaric and chicoric acids, isoquercetin, and luteolin, consistent with the upregulation of a few genes related to the biosynthetic pathway of phenolic compounds (4C3H and DFR). The study highlights that different <i>sf</i> may significantly affect the EUE as well as crop nutritional properties.