Acute kidney injury (AKI) involves oxidative stress, inflammation, and metabolic toxin accumulation, leading to renal dysfunction and systemic metabolic disorders. Current treatments provide limited efficacy and fail to address the interplay between renal and intestinal pathologies. Here, we present a noninvasive dual-action oral platform that integrates systemic and gut-targeted therapeutic effects to restore homeostasis along the gut–kidney axis. The system employs a choline–quercetin ionic liquid (ChQ-IL) as the active pharmaceutical ingredient, encapsulated within pH-responsive, calcium-crosslinked alginate microparticles (Alg MPs). These MPs are fabricated using an interfacial microfluidic solidification technique developed in this study to ensure uniformity and scalability. ChQ-IL markedly enhances quercetin solubility and intestinal permeability while preserving its antioxidant and anti-inflammatory activities, whereas Alg MPs provide gastric protection, controlled intestinal release, and prebiotic-like benefits. In a glycerin-induced AKI mouse model, oral administration of ChQ-IL@Alg MPs significantly alleviates oxidative stress, inflammation, renal injury, and uremic toxin accumulation through systemic delivery, while concurrently enhancing short-chain fatty acid production, restoring gut metabolic balance, and preventing body weight loss via gut-targeted effects. This dual-action modulation of the gut–kidney axis establishes ChQ-IL@Alg MPs as a scalable, safe, and patient-compliant oral platform that offers integrated renal and metabolic protection for next-generation AKI therapy.