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Cold atmospheric plasma (CAP) interacting with tumor cells, and finally, leading to selective cell death has opened new horizons in cancer therapy. Despite significant progress in modern cancer treatment using immunologic and targeted therapies melanoma and glioblastoma (GBM) presenting as brain metastases or primary tumor with poor prognosis are still a therapeutic challenge. The aim of this paper was to evaluate the potential of CAP (indirect treatment) in combination with the chemotherapeutics bleomycin, paclitaxel, and dacarbazine to inhibit proliferation on human melanoma and GBM cells in vitro . Cell lines of mouse melanoma (B16) were exposed for 1, 4, 12, 24, and 48 h, and of human melanoma (A375) and GBM (A172) for 24 h to bleomycin, dacarbazine, and paclitaxel together with plasma activated phosphate buffered saline. Directly after exposure, cell proliferation after single (CAP and chemotherapeutic) or combined (CAP plus chemotherapeutic) treatment was assessed by cytotoxicity assay. Indirect CAP treatment of cell lines of GBM and melanoma was followed by a strong reduction of proliferation most prominent after 24 and 48 h exposure. With all drugs maximal reduction was achieved when drug-CAP combinations were used. Combination with CAP treating B16 melanoma cells reached 98% (48 h, combined with paclitaxel), A375 melanoma cells 82% (24 h, combined with bleomycin), and GBM cells 96% (24 h, combined with paclitaxel). The combination of chemotherapy with CAP as indirect treatment may be beneficial in therapy of melanoma and GBM by enhanced tumor reduction and less drug toxicity of chemotherapeutics.