<p>Melanoma ranks 17th among the most frequently diagnosed cancers, with an upward trend in incidence. Treatment of this cancer is based on surgical removal of the lesion, but when metastases or recurrence occur, immunotherapy or chemotherapy is used. Most of the drugs used are characterized by numerous side effects or drug resistance that appears after some time of use. Therefore, multi-drug therapy is more often considered. The aim of the study was to assess the nature of the pharmacodynamic interaction of five different cytostatics (in a fixed dose ratio of 1:1) using a mathematical-statistical method—isobolographic analysis. The experiments were conducted on four human malignant melanoma cell lines (A375, SK-MEL28, FM55M2, FM55P) and studied all possible (ten) pairs of combinations of five standard cancer chemotherapy drugs (based on the MTT test): cisplatin, mitoxantrone, docetaxel, vemurafenib, and selumetinib. Our experiments showed that the most advantageous combination was the combination of vemurafenib with docetaxel for human melanoma lines—statistically significant synergy interaction for three cell lines. Also noteworthy are the combinations: cisplatin with mitoxantrone, vemurafenib with selumetinib, and vemurafenib with mitoxantrone. From a therapeutic point of view, the worst combination is cisplatin with docetaxel and cisplatin with selumetinib (interaction with a tendency to antagonism for the two cell lines). Monotherapy for melanoma does not produce good results, so the best drug combinations are sought, which would improve long-term, durable patient response and overcome drug resistance. It would also be good if the combination used caused fewer side effects than monotherapy, and this could be achieved in the case of using synergistic combinations.</p>