The smart design of nanoparticles with varying surfaces may open a new avenue for potential biomedical applications. Consequently, several approaches have been established for controlled synthesis to develop the unique physicochemical properties of nanoparticles. However, many of the synthesis and functionalization methods are chemical-based and might be toxic to limit the full potential of nanoparticles. Here, curcumin (a plant-derived material) based synthesis of gold (Au) nanoparticles, followed by the development of a suitable exterior corona using isoniazid (INH, antibiotic), tyrosine (Tyr, amino acid), and quercetin (Qrc, antioxidant), is reported. All these nanoparticles (Cur-Au, Cur-AuINH, Cur-AuTyr, and Cur-AuQrc) possess inherent peroxidase-mimicking natures depending on the surface corona of respective nanoparticles, and they are found to be excellent candidates for free radical scavenging action. The peroxidase-mimicking nanoparticle interactions with red blood cells and mouse macrophages confirmed their hemo- and biocompatible nature. Moreover, these surface-engineered Au nanoparticles were found to be suitable in subsiding key pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). The inherent peroxidase-mimicking behavior and anti-inflammatory potential without any significant toxicity of these nanoparticles may open new prospects for nanomedicine.