Phthalides, mainly isolated from two genera: Ligusticum and Angelica of the Apiceae (syn Umbelliferae) family, are thought to be a potent natural compound with many therapeutic effects, such as antiplatelet, antitussive, antinociceptive, anti-inflammatory, antibacterial, antiviral, and immunosuppressive activities. They also have antifungal, antioxidant, and anticancer activities. Phthalides are responsible for the characteristic odor of celery. Since ancient times, phthalides containing plants have been used in Asia, Europe, and North America as traditional medicines and food flavoring agents. In this review, we have provided the data regarding the mechanisms of action related with phthalides on different cancer cells, their chemopreventive properties, and their possible therapeutic potential against various types of human cancer. Our attempt is to make a case for the use of phthalide and their derivatives as one of the plant-based compounds in targeting metabolic treatment of cancer diseases.