Cancer is a highly significant medical concern, as it is the second most prevalent cause of mortality after cardiovascular diseases. It arises due to dysregulated cell cycle control, leading to a gradual decline in cellular differentiation and unrestricted cellular proliferation. Therefore, the primary objective for researchers is to develop a cancer treatment that addresses drug resistance while providing effective therapeutic benefits and minimizing side effects. Benzimidazole has garnered significant attention because it serves as an auxiliary isostere of nucleotides, which are found in several natural and biologically active molecules. Benzimidazole compounds possess a privileged pharmacophore that exhibits various pharmacological actions. Several benzimidazole derivatives exhibit dual or multiple anticancer properties through diverse mechanisms, focusing on specific compounds or employing strategies that are not gene specific. Furthermore, many drugs based on benzimidazole have previously been approved to treat cancer. This comprehensive review encompasses the most important reports on various benzimidazole hybrids, highlighting their anticancer significance, mechanism of action, and structure-activity relationships from 2005 up to 2025. These provide valuable knowledge for designing effective anticancer drugs.