In recent years, natural products have been significantly deployed for the treatment of human diseases [1,2]. Phytochemicals, secondary metabolites, and bioactive compounds have emerged as alternatives in the treatment of diseases [3]. Nature is considered a rich source of natural products with health-promoting impacts on humans. Disease management, prevention, and promotion of health can be obtained by natural products [4], [5], [6]. Natural products and phytochemicals have demonstrated a number of health-promoting impacts, including antioxidant, anti-inflammatory, and anti-apoptotic effects [7]. The treatment of cancer has been accelerated by the application of natural products [8]. The pioneers for the application of natural products in the treatment of diseases are ancient Greeks, Arabs, Chinese, and Indians and they have utilized phytochemicals for the treatment of cancer and other diseases [9,10]. Curcumin, resveratrol, and quercetin are considered as natural compounds for the treatment of cancer, while a number of compounds, including paclitaxel and doxorubicin, have obtained FDA approval [11]. The distinct pharmacological activities of these compounds and their complicated structures, have made promising compounds for the regulation of biological mechanisms, and they can solve a number of synthetic drug problems, such as oral administration stability [12]. However, the deployment of natural products in medicine is not wide and is restricted by a number of factors, including poor pharmacokinetic and pharmacodynamic features, low solubility, limited stability, and poor bioavailability [13]. Furthermore, the recognition and extraction of natural products are demanding and not affordable, forcing pharmaceutical companies to invest conservatively in natural-based products [14]. However, there is much hope in the field of drug discovery, to use natural products as alternatives to the previously used anticancer drugs. Despite this optimism, significant challenges persist with previously used natural products in cancer treatment, particularly regarding chemoresistance.. Recent highlights have shown that natural products can be utilized as compounds to increase the drug sensitivity of cancer cells [15]. Therefore, natural products can propose more hope for cancer patients, if they are used widely at the clinical level. In the current review, there will be a focus on the application of natural products for the regulation of tumor microenvironment (TME) and targeting the macrophages as the most abundant cells in this space. In addition to cancer therapy, this review will summarize how the application of natural products can alleviate macrophage-mediated inflammation for the treatment of pathological events.