Cancer stem cells (CSCs) belong to a small subset of tumor cells with self-renewal and differentiation capacity, implicating the initiation and progression of cancer and metastasis. CSCs are relatively resistant to traditional cancer treatments like chemotherapy and radiation. These are the very cells that initiate tumor development, progression, metastasis, and recurrence, making cancer therapy a daunting task. Bioactive compounds (naturally derived molecules from plants mainly belonging to the medicinal plant family) come into the picture as potential candidates for CSCs. Such phytochemicals (such as terpenoids, alkaloids, and flavonoids) have been reported to disrupt specific signaling pathways indispensable for the proper stemness, self-renewal, and survival of CSCs. Key pathways are pivotal in CSCs maintenance, i.e., Wnt/β-catenin, Notch, and Hedgehog. These pathways can be targeted by bioactive compounds such as resveratrol, curcumin, and hesperetin. The interaction between immune evasion, the role of tumor-associated macrophages (TAMs), and other constituents of CSC-stromal cells remains a challenge for targeting the CSC population. Three innovative approaches to counteract prerequisite cancer stem cell resistance are bioactive-based therapeutics associated with conventional drugs, nanotechnology-based delivery techniques, and immunotherapy.