AbstractA fascinating oncology target is the serine/threonine‐specific protein kinase B‐Raf, which is a component of the MAPK pathway. A new series of triazolo oxadiazole derivatives have been identified as the primary scaffold of small molecule B‐Raf inhibitors. Twelve derivatives (7a–l) of triazolo oxadiazole hybrids were synthesized and characterized by spectral data. The evaluation of physicochemical and pharmacokinetic parameters demonstrated that the compounds′ solubility, lipophilicity, and compliance with Lipinski's rule are all within acceptable ranges. The anti‐proliferative capability of the synthesized derivatives was evaluated by screening them against the human melanoma cell lines Skmel‐23 and A375, which express B‐Raf in their wild‐type and mutant forms, respectively. The IC50 values differed significantly from those of the conventional doxorubicin. The IC50 values for compounds 7b and 7e against Skmel‐23 were determined to be 26.95 and 76.17 μM, respectively. The compounds 7b and 7c inhibited A375 cells at IC50 concentrations of 16.64 and 78.1 μM, respectively. Therefore, these compounds were subjected to morphological screening to detect changes in cell morphology and evaluate their apoptotic potential. The compound 7b was found to significantly inhibit both cell lines and is therefore a promising therapeutic candidate for targeting both wild‐type and mutant B‐Raf forms.