Ample data pertaining to the use of MDSCs have been documented. However, the potency of natural products in targeting MDSCs in the light of the tumor immune microenvironment (TME) has not been discussed vividly. The current review is an amalgamation of the documented literature pertaining to the effectiveness of various natural products supported by in silico experimental data. The combination of bioinformatics to wet bench experimentation with natural products against cancer specifically targeting MDSCs can be a promising approach to mitigate cancer.