Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.