Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts immune function by activating inflammatory pathways related to disease severity. Understanding virus-induced inflammation is crucial for developing anti-coronavirus disease 2019 (COVID-19) therapies. This study used principal component analysis, heatmaps, and other tools to examine mitogen-activated protein kinase (MAPK) pathway gene expression, and found that alterations in MAPK pathway genes were correlated with immune response changes. Further analysis linked P38-related gene expression to clinical symptoms, with transcriptomic data showing a strong association between MAPK gene expression changes and SARS-CoV-2 infection. In infected cell models, P-P38 protein and inflammatory factors were significantly upregulated. Analysis of the GSE217948 dataset showed a significant correlation between plasma markers (interferon inducible protein 10 (IP-10) and interleukin (IL)-6) and symptoms (fever and fatigue). Activation of P38 appears to release inflammatory factors tied to these symptoms making P38 as a key pathway in virus-induced inflammation. Forsythin (KD-1), an anti-inflammatory compound from forsythia showed efficacy against SARS-CoV-2, inhibiting replication, reducing P38 levels, and lowering inflammatory markers (IL-6, IL-8, IP-10, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1)) in both cell and animal models. In specific cell models, KD-1 blocked P38 activation, thereby reducing inflammation. In a P38 overexpression model, KD-1 decreased P38 phosphorylation and downstream inflammatory proteins. This study identifies the P38 pathway as a therapeutic target for COVID-19, supporting KD-1’s potential in mitigating virus-induced inflammation and guiding further research into anti- inflammatory treatments for respiratory viruses.