The p38 mitogen-activated protein kinases (p38 MAPK) is a 38kD polypeptide recognized as the target for many potential anti-inflammatory agents. Accumulating evidence indicates that p38 MAPK could perform many roles in human disease pathophysiology. Therefore, great therapeutic benefits can be attained from p38 MAPK inhibitors. Ginseng is an exceptionally valued medicinal plant of the family Araliaceae (Panax genus). Recently, several studies targeted the therapeutic effects of purified individual ginsenoside, the most significant active ingredient of ginseng, and studied its particular molecular mechanism(s) of action rather than whole-plant extracts. Interestingly, several ginsenosides: ginsenosides compound K, F1, Rb1, Rb3, Rc, Rd, Re, Rf, Rg1, Rg2, Rg3, Rg5, Rh1, Rh2, Ro, notoginsenoside R1, and protopanaxadiol have shown to possess great therapeutic potentials mediated by their ability to downregulate p38 MAPK signaling in different cell lines and experimental animal models. Our review compiles the research findings of various ginsenosides as potent anti-inflammatory agents, highlighting the crucial role of p38 MAPK suppression in their pharmacological actions. In addition, in silico studies were conducted to explore the probable binding of these ginsenosides to p38 MAPK. The results obtained proposed p38 MAPK involvement in the beneficial pharmacological activities of ginsenosides in different ailments.