Extracellular ATP is a key component of the tumor microenvironment, where it promotes cancer progression by activating the P2X7 receptor (P2X7R). Prolonged receptor stimulation triggers the release of pro-tumorigenic extracellular vesicles and soluble factors, including IL-1β, VEGF, and TGFβ. Here, we report the design and characterization of novel triazole- and benzamide-based negative allosteric modulators of P2X7R. Among these, compounds 5 and 9 showed nanomolar affinity for the human receptor ( K _i = 80 nM and 3.17 nM, respectively) and effectively inhibited calcium influx (IC ₅₀ 370 nM and 47 nM, respectively). Molecular docking supported distinct binding modes for the two scaffolds, aligning them with known allosteric inhibitors through interactions with Lys297, Asp92, and hydrophobic subpockets. Compounds 5 and 9 displayed favorable metabolic stability in mouse liver microsomes and efficiently blocked P2X7R-dependent signaling in melanoma, glioblastoma, and colon carcinoma cells. Treatment with both compounds significantly reduced tumor cell proliferation, invasiveness, and extracellular vesicle release, with efficacy comparable to or greater than that of the reference antagonist A740003. In vivo, both molecules suppressed melanoma growth in syngeneic mice and modulated cytokine levels in the TME by increasing IFN-γ while reducing VEGF, IL-1β, and TGF-β. These findings identify compounds 5 and 9 as potent, selective, and metabolically stable P2X7R antagonists with translational potential as anticancer agents targeting both tumor growth and extracellular vesicle-mediated communication.