A novel series of triazolopyrimidine derivatives (5a–d and 6a–c) was synthesized via a green NiO nanoparticle-catalyzed protocol under mild conditions, affording the target compounds in good to excellent yields. The NiO nanoparticles exhibited high catalytic efficiency, attributed to their nanoscale features and porous structure, as confirmed by physicochemical characterization. Structural elucidation of the synthesized compounds was achieved using standard spectroscopic techniques. Computational studies, including density functional theory and molecular docking, were employed to evaluate the reactivity and potential multi-target activity of the compounds against key proteins involved in gout pathogenesis. The results revealed that selected derivatives exhibited favourable binding affinities toward multiple inflammatory targets, supported by stable protein– ligand interactions in molecular dynamics simulations. These findings suggest that the synthesized compounds may serve as potential multi-target candidates for gout therapy and warrant further biological investigation.