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<b>Background:</b> The tumor microenvironment (TME) is a dynamic ecosystem that critically shapes tumor progression, immune escape, and therapeutic responses. <i>Hedyotis diffusa</i> Willd (HDW) has long been used in East Asian medicine for conditions associated with inflammation and malignancy, yet its immunological and microenvironmental mechanisms have not been systematically synthesized. <b>Methods:</b> A scoping review of preclinical studies (2016-2025) was conducted following the Arksey-O'Malley framework and PRISMA-ScR guidance to systematically map experimental evidence on the antitumor, immune-related, and TME-associated effects of HDW. To complement and interpret these heterogeneous experimental findings at a systems level, a network pharmacology analysis was performed to identify bioactive compounds, predict their putative protein targets, and assess their convergence on immune- and microenvironment-related signaling networks through protein-protein interaction and pathway enrichment analyses. <b>Results:</b> Fifty-nine studies met eligibility criteria, encompassing in vitro and in vivo models across diverse cancer types. Experimental evidence from preclinical models showed that HDW extracts and bioactive fractions consistently suppressed proliferation, induced apoptosis and ferroptosis, inhibited epithelial-mesenchymal transition (EMT) and angiogenesis, and enhanced cytotoxic lymphocyte activity, while attenuating tumor-associated inflammation. In parallel, in silico network analysis identified 94 intersecting immune- and TME-related targets and revealed a densely connected interaction network centered on PI3K-Akt, STAT3, EGFR, and SRC. Enrichment analyses highlighted receptor tyrosine kinase signaling, inflammatory pathways, metabolic regulation, and focal adhesion as dominant functional themes. <b>Conclusions:</b> HDW acts as a multi-target botanical agent that integrates direct cytotoxicity with immune activation and TME remodeling. Network-in-formed interpretation indicates that the modulation of PI3K-Akt-STAT3 signaling is a common mechanistic axis linking experimental observations.