Background: Immunomodulation is the modification of immune responses to control disease progression. While the synthetic immunomodulators have proven efficacy, they are coupled with toxicity and other adverse effects, and hence, the efforts were to identify natural phytochemicals with immunomodulatory potential. Objective: To understand the immunomodulatory properties of various phytochemicals and investigate them in Echinacea species extracts using an in silico approach. Methodology: Several scientific database repositories were searched using different keywords: “Phytochemicals,” “Alkaloids,” “Polyphenols,” “Flavonoids,” “Lectins,” “Glycosides,” “Tannins,” “Terpenoids,” “Sterols,” “Immunomodulators,” and “Human Immune System” without any language restriction. Additionally, the study specifically investigated the immunomodulatory properties of Echinacea species extracts using gene expression analysis of GSE12259 from NCBI-GEO through the Bioconductor package GEOquery and limma. Results: A total of 182 studies were comprehensively analyzed to understand immunomodulatory phytochemicals. The in silico analysis highlighted key biological processes (positive regulation of cytokine production, response to tumor necrosis factor) and molecular functions (cytokine receptor binding, receptor-ligand activity, and cytokine activity) among Echinacea species extracts contributing to immune responses. Further, it also indicated the association of various metabolic pathways, i.e., pathways in cancer, cytokine-cytokine receptor interaction, NF-kappa B, PI3K-Akt, TNF, MAPK, and NOD-like receptor signaling pathways, with immune responses. The study revealed various hub targets, including CCL20, CCL4, GCH1, SLC7A11, SOD2, EPB41L3, TNFAIP6, GCLM, EGR1, and FOS. Conclusion: The present study presents a cumulative picture of phytochemicals with therapeutic benefits. Additionally, the study also reported a few novel genes and pathways in Echinacea extracts by re-analyzing GSE 12259 indicating its anti-inflammatory, anti-viral, and immunomodulatory properties.