Globally, helminthiasis is one of the most prevalent causes of mortality and morbidity and threatens humans and livestock. An effective anthelmintic vaccine is also lacking. As a result, nematode infections are mostly treated with chemotherapy, such as benzimidazoles, but due to drug resistance, their effectiveness is limited.This review focuses on previously synthesized benzimidazole derivatives and their structure-activity relationships related to effectiveness in treating helminthiasis. For example, structural modifications have been introduced in developing benzimidazole-based drugs for helminthiasis chemotherapy at positions 2, 5, or 6, whereas positions 4 and 7 should not be altered. For benzimidazole to be effective as an anthelmintic, it must have a free hydrogen atom at its 1-position.Using the results of this review as a guide, we have proposed designs that will allow the development of more effective and less toxic drugs for helminthiasis chemotherapy. Despite this, a better understanding of parasite biochemistry and host-parasite interactions is necessary to develop innovative lead molecules with greater efficacy.