Combination chemotherapy is a common practice in clinical management of malignancy. Synergistic therapeutic outcome is only achieved when tumor cells are exposed to cells in an optimal ratio. However, due to diverse physicochemical properties of drugs, no free drug cocktails or nanomaterials are capable of co‐loading and co‐delivering drugs at an optimal ratio. Herein, we develop a novel nano‐platform with precise ratiometric co‐loading and co‐delivery of two hydrophilic drugs for synergistic anti‐tumor effects. Based on previous work, we utilize a solvent displacement method to ratiometrically load dioleoyl phosphatidic acid (DOPA)‐gemcitabine monophosphate (GMP) and DOPA coated cisplatin‐precipitate nanocores into the same PLGA NP. These cores are designed to have similar hydrophobic surface properties. GMP and cisplatin are engineered into PLGA NP at an optimal synergistic ratio (5:1, mol:mol) with over 70% encapsulation efficiency and were ratiometrically taken up by tumor cells in vitro and in vivo. These PLGA NP exhibit synergistic anti‐cancer effects in a stroma‐rich bladder tumor model. A single injection of dual drugs in PLGA NP can significantly inhibit tumor growth. This nanomaterial‐system solves problems related to ratiometric co‐loading and co‐delivery of different hydrophilic moieties and provides possibilities for co‐loading hydrophilic drugs with hydrophobic drugs for combination therapy. A novel nano‐platform with ratiometric loading and delivery of multiple hydrophilic drug moieties is demonstrated. Hydrophilic cisplatin and gemcitabine monophosphate are standardized to a similar hydrophobicity through loading into lipid‐coated calcium phosphate and cisplatin cores, respectively. Precise ratio‐controlled loading and delivery is achieved by incorporating these cores into PLGA NPs. These ratiometric combinations lead to the maximal synergistic anticancer effect.