Leaf rust of wheat, incited by fungus Puccinia triticina is an economically important disease. It is currently highly destructive leading to significant yield losses. Many disease resistant wheat varieties have been developed but unable to maintain resistance over a long time due to rapidly evolving effector proteins by the pathogen, which escapes interaction with plant R-genes over time. Synthetic fungicides are available for control of the disease but they are biohazardous and eco-unfriendly. Mitogen Activated Protein Kinases (MAPKs) have been found in all organisms, including fungi, and are involved in the transmission of a variety of extracellular signals to manage growth and differentiation processes. The present study aimed to identify natural fungicide like molecules that can inhibit MAPKs machinery involved in growth, mating, and virulence of pathogen through molecular docking and dynamics simulation study. A high-quality structural model of MAPK1 protein was predicted and used to dock 110 natural compounds. Two compounds viz. Cynaroside and Prodelphinidin showed a more binding affinity with MAPK1. Therefore, the docked complex structure of these two compounds and MAPK1 was further subjected to molecular dynamics simulation to evaluate its stability and binding nature during protein–ligand interaction. Based on the result analysis, it was predicted that they have efficient and stable binding nature, and better cell permeability properties. It may be used as a natural fungicide against leaf rust and other fungal diseases, only after further validation in lab and field conditions.