Abstract: Objective: To develop potential formulations for alleviating hyperuricemia, we screened approximately 10 medicinal and food homologous ingredients, including Apium graveolens L., Lycium ruthenicum Murray, and Inonotus obliquus, and explored their biological functions and underlying mechanisms. Methods: Based on the quantitative analysis from in vitro antioxidant capacity and xanthine oxidase inhibition for each candidate, the optimized formulation containing different ingredients, namely the homologous combinations 1 (FMHC1), could be obtained using the “Uniform Design Method”. Further, the in vitro digestion behavior of FMHC1 was investigated. Besides, the protection efficiency on the hyperuricemia cell model that was established by inducing HK-2 cells with adenosine and xanthine oxidase was evaluated, by determining the levels of uric acid in cell supernatant, pro-inflammatory cytokines (IL-6, TNF-α), anti-inflammatory cytokines (IL-10, TGF-β), as well as the oxidative stress markers (MDA, CAT, SOD, GSH-Px). Results: The ideal formulation for FMHC1 was 41% Apium graveolens L., 39% Inonotus obliquus, 10% Lycium ruthenicum Murray, 5% Lonicera japonica Thunb, and 5% Stigma Maydis. The experimental results showed that FMHC1 displayed high bioavailability, where the inhibitory efficiency for xanthine oxidase was decreased by only 4.89%±1.02% (gastric phase) and 11.08%±1.59% (intestinal phase) after in vitro digestion. Moreover, the uric acid level in the hyperuricemia cell model was down-regulated by 35.52%. These occurrences might be attributed to the ameliorated inflammatory responses through regulation of cytokines. Upon the administration, the IL-6 and TNF-α were upregulated by 25.82% and 66.51%, respectively, whereas the corresponding IL-10 and TGF-β were downregulated by 73.10% and 49.18%. Besides, the antioxidant capacity was significantly enhanced. As a result, about 61.20% loss for MDA level in cell line occurred, and the activities for CAT, SOD, and GSH-Px were enhanced by 2.86, 0.63, and 2.00 times, respectively. Conclusion: The screened FMHC1 demonstrates great potential in dealing with hyperuricemia through multiple pathways, and could be considered to be a promising diet in disease intervention.