Cisplatin is a highly toxic material used clinically as a potent chemotherapeutic. While effective against some cancers, toxicity limits widespread use and low solubility confounds delivery. To formulate a better tolerated and more water-soluble form of cisplatin, we designed a rapid expansion of supercritical solutions (RESS) technique with supercritical carbon dioxide (sc-CO2) to collect nanoclusters of cisplatin embedded in dry ice, in a dual-stage collection vessel cooled to liquid nitrogen temperature. These nanoclusters were solubilized in deionized water and further concentrated (up to 51.3 mM) by a Rotovap process, yielding stable cisplatin solutions with solubility up to 15 × (w/w) greater than that of normal cisplatin. Extensive material characterizations of the solutions were carried out to determine any chemical and/or structural changes of the RESS-processed cisplatin. In vitro cytotoxicity studies of these aqueous solutions showed increased cell viability and early apoptosis compared to equivalent concentrations of standard cisplatin solutions. In vivo studies using zebrafish embryos revealed that standard cisplatin solutions were acutely toxic and caused death of rapidly proliferating cells compared to RESS-processed cisplatin, which were better tolerated with reduced general cell death. Increased water solubility and matched chemical identity of RESS-processed aqueous cisplatin solutions indicate the potential to open up novel drug-delivery routes, which is beneficial for new pharmaceutical design and development.