Urolithiasis is a complex and multifactorial disease characterized by the formation of calculi at the urinary tract level. Conventional therapeutic prophylaxis relies on the use of Ca-blockers, alkalis, diuretics, and anti-edema agents, but their prolonged utilization is often limited by several side effects. In this scenario, the aim of the present work was the design of an innovative multi-component nutraceutical formulation (NF) for the management of urinary stones consisting of a synergistic combination of natural aqueous extracts ofOreganum vulgareL. (1% of saponin),Urtica dioica(0.8% of β-sitosterol),Phyllanthus niruri(15% of tanninsw/w), andCeterach officinarumin association with bromelain, K, and Mg citrate. To assess the potential of NF also in the treatment of uric acid (UA) stones, the effects on the expression of the cellular UA transporters OAT1 and URAT1 were investigated in a renal tubular cell line. In addition, the myorelaxant effect of NF was investigated in a human pulmonary artery smooth muscle cell (HPASMC) model resulting in a decreased muscle contractility of −49.4% (p< 0.01) compared to the control. The treatment with NF also showed a valuable inhibition of in vitro calcium-oxalate crystal formation, both in prevention (−52.3% vs. control,p< 0.01) and treatment (−70.8% vs. control,p< 0.01) experiments. Finally, an ischemic reperfusion rat model was used to evaluate the NF anti-edema effects, resulting in a reduction in the edema-related vascular permeability (Normalized Gray Levels, NGL = 0.40 ± 0.09,p< 0.01, −67.1% vs. untreated rats). In conclusion, the present NF has shown to be a promising natural alternative for managing urinary tract stones.