To examine the utilization of metal oxide nanoparticles (NPs) in different commercial products, this work focuses on the determination of cost-effective and scalable synthesis protocols. The solvothermal protocol is well-known as a scalable method but has recently been shown to lack economic feasibility. The mechanochemical method has recently been recognized to be a more economic and environmentally friendly substitute for the solvothermal method. In this study, zinc oxide nanoparticles (ZnO NPs) and copper oxide nanoparticles (CuO NPs) were synthesized using two (aqueous and organic) solvothermal (wet) methods and two (manual and automated) mechanochemical (dry) methods. The four methods were evaluated and compared. The automated mechanochemical method generated a significantly higher yield of ZnO NPs (82%) and CuO NPs (84%) using the least energy and time. However, the prepared ZnO NPs displayed higher cytotoxicity against Vero E6 cells when compared to that of CuO NPs. Because of their low cytotoxicity, CuO NPs synthesized via the automated mechanochemical method were selected for application onto cotton fabrics. Lower cytotoxicity was observed for CuO NPs treated fabrics with an IC