<p><b>Abstract:</b><b></b></p><p><b><i>Objective:</i></b> To explore the target of anti-knee osteoarthritis (KOA) in the effective chemical compounds of piper longum L based on network pharmacological methods.<b></b></p><p><b><i>Methods</i></b>: The active chemical compounds of piper longum L were collected employing database retrieval on TCMSP, TCM-PTD, and literature mining. The Swiss Target Prediction service predicts the targets of active chemical compounds, and at the same time, the targets of the drugs treating knee osteoarthritis were collected by retrieving the OMIM and CTD databases. The targets were subjected to an alignment analysis to screen out piperine and we simulated the binding sites in vivo of compounds and proteins via AutoDock. After that, the rat models of knee osteoarthritis were established. The rats in model groups were given piperine treatment. The verification of the anti-KOA target PPARG and MAPK1 was done by Western blot and co-immunoprecipitation.</p><p><b><i>Results</i></b><i>: </i>Nine active ingredients were predicted. According to Lipinski's rule, piperine was speculated as a possible active ingredient. According to the possible targets of piperine and the KOA's possible targets, three co-targets of them were confirmed, PPARG and MAPK1 were related to knee osteoarthritis (KOA). Molecular docking results show that piperine can hinder the binding of PPARG protein ARG-212 and GLN-420 amino-acid residues to each other. After 20 weeks of piperine treating, Western blot found that piperine can significantly increase the expression level of PPARG and reduce the expression level of MAPK1 in model rats. The endogenous interaction between PPARG and MAPK1 was verified by co-immunoprecipitation.</p><p><b><i>Conclusion</i></b><i>:</i> Piper longum L can regulate the progression of knee osteoarthritis (KOA) by its active ingredient piperine，can affect the expression of PPARG and MAPK1 proteins, and PPARG and MAPK1 proteins have endogenous interactions.</p>