Two anti-melanoma drugs, lenvatinib and temozolomide, were cocrystallized to obtain two drug-drug cocrystal solvates, TMZ-LEN·MeOH (1 : 1 : 1) and TMZ-LEN·EtOH (1 : 1 : 1). They were fully characterized by XRD and thermal analyses, NMR and FTIR spectroscopy. The crystal structure of TMZ-LEN·MeOH shows that LEN is simultaneously linked to TMZ and methanol via hydrogen bonding interactions. Stability, dissolution and compaction evaluations highlight that the formation of the drug-drug cocrystal not only improves the physicochemical stability and tabletability of TMZ, but also optimizes the dissolution behavior of LEN and TMZ, respectively. Therefore, TMZ-LEN·MeOH and TMZ-LEN·EtOH have great potential to be developed as a drug combination, which will address the problematic properties of LEN and TMZ, for the treatment of melanoma patients with brain metastases. Cocrystallization of two anti-melanoma drugs, lenvatinib and temozolomide, resulted in two drug-drug cocrystal solvates presenting improved performance in terms of stability, dissolution, and tabletability, which show great potential to be developed as a drug combination.