Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput screening assay for identification of synergistic combinations between broadly applied platinum-based chemotherapeutics and drugs from a library composed of 1280 chemically and pharmacologically diverse (mostly FDA approved) compounds. The assay was performed on chemoresistant cell lines derived from lung (A549) and pancreatic (PANC-1) carcinoma, where platinum-based combination regimens are currently applied though with limited success. The synergistic combinations identified during the screening were validated by synergy quantification using the combination index method and via high content fluorescent microscopy analysis. New promising synergistic combinations discovered using this approach include compounds currently not used as anticancer drugs, such as cisplatin or carboplatin with hycanthone and cisplatin with spironolactone in pancreatic carcinoma, and carboplatin and deferoxamine in non-small cell lung cancer. Strong synergy between cisplatin or carboplatin and topotecan in PANC-1 cells, compared to A549 cells, suggests that this combination, currently used in lung cancer treatment regimens, could be applied to pancreatic carcinoma as well. Several drugs used to treat diseases other than cancer, including pyrvinium pamoate, auranofin, terfenadine and haloprogin, showed strong cytotoxicity on their own and synergistic interactions with platinum drugs. This study demonstrates that non-obvious drug combinations that would not be selected based on complementary mechanisms can be identified via high-throughput screening.