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Advanced knowledge about the role of tumor microenvironment (TME) in cancer progression has opened various ways to target the vast signaling pathways for cancer treatment. Failures of the currently used drugs have raised out the need to look for novel drugs which can target various crucial aspects of cancer progression (e.g., angiogenesis, uncontrolled cell division, and metastasis). Phytochemicals behaving as potent anticancer agents shows promise as therapeutics. Various phytochemicals, such as curcumin, Epigallocatechin Gallate (EGCG), resveratrol, plumbagin, genistein, and others, have been identified with modulatory effect on TME. These phytochemicals often target the molecular pathways that reside in the tumor vicinity associated with endothelial cells, cancer-associated fibroblasts, immune cells, mesenchymal stem cells, other cell types, vascular and lymphatic networks, and extracellular matrix which are important for tumor progression and development. Some phytochemicals also target the internal signaling pathways, including STAT3, NF-қB, ERK-1/2, and PI3K/Akt signaling of noncancer cell, residing in the microenvironment, and thus inhibiting the supportive effect from these cells in tumor development. However, much information needs to be acquired before using these phytochemicals in cancer treatment. The primary objective of this review is to provide a better knowledge about the role of TME in cancer progression and development, focusing on the different targets which can be used for therapeutic approach, and then to give a brief account on some known phytochemicals to date, which have shown remarkable TME modulatory effects. PRACTICAL APPLICATIONS: For the use of phytochemicals as therapeutics, it is highly recommended that their precise target should be known; therefore studies should be encouraged such that the effects of these phytochemicals can be evaluated on the individual cellular level like how the phytochemical is targeting the tumor-associated macrophage, or any other cell residing in the tumor microenvironment (TME), and the compound should target a specific component of TME to avoid off target effects.