High-pressure homogenization (HPH) was used to increase the water solubility of quercetin crystals, which exhibit antioxidant, anti-inflammatory, and anticancer properties but poor water solubility and oral bioavailability. The improved water solubility of quercetin by HPH treatment could be attributed to very fine suspensions produced in the nanometric range (similar to 400 nm) and loss of crystallinity caused by mechanical friction and stresses, which were verified by particle size measurements, differential scanning calorimetry (DSC), atomic force microscopy (AFM), and scanning electron microscopy (SEM) results. Easily water redispersible powders were fabricated by the combination of HPH treatment and spray-drying process when maltodextrin was used as a carrier agent. HPH-treated spray-dried powders exhibited higher antioxidant activities than nontreated samples through increased water dispersity in terms of radical scavenging activity, reducing ability, and oxygen radical absorbance capacity determinations. This study suggests that the combination of HPH treatment with spray-drying would be an excellent processing method for the development of quercetin-based functional food products.