Cancer is one of the major leading causes of death worldwide. Accumulating evidence suggests a strong relationship between specific dietary habits and cancer development. In recent years, a food-based approach for cancer prevention and intervention has been gaining tremendous attention. Among diverse dietary and medicinal plants, lotus (Nelumbo nucifera Gaertn., family Nymphaeaceae), also known as Indian lotus, sacred lotus or Chinese water lily, has the ability to effectively combat this disease. Various parts of N. nucifera have been utilized as a vegetable as well as an herbal medicine for more than 2000 years in the Asian continent. The rhizome and seeds of N. nucifera represent the main edible parts. Different parts of N. nucifera have been traditionally used to manage different disorders, such as fever, inflammation, insomnia, nervous disorders, epilepsy, hypertension, cardiovascular diseases, obesity, and hyperlipidemia. It is believed that numerous bioactive components, including alkaloids, polyphenols, terpenoids, steroids, and glycosides, are responsible for its various biological and pharmacological activities, such as antioxidant, anti-inflammatory, immune-modulatory, antiviral, hepatoprotective, cardioprotective, and hypoglycemic activities. Nevertheless, there is no comprehensive review with an exclusive focus on the anticancer attributes of diverse phytochemicals from different parts of N. nucifera. In this review, we have analyzed the effects of N. nucifera extracts, fractions and pure compounds on various organ-specific cancer cells and tumor models to understand the cancer-preventive and therapeutic potential and underlying cellular and molecular mechanisms of action of this interesting medicinal and dietary plant. In addition, the bioavailability, pharmacokinetics, and possible toxicity of N. nucifera-derived phytochemicals, as well as current limitations, challenges and future research directions, are also presented.