Purpose <p>Cefixime (CEF) demonstrates strong activity against <i>Streptococcus pyogenes</i> despite its limited dermal penetration and low drug bioavailability, as per Biopharmaceutics Classification System (BCS). The study aimed to develop a nanoparticle system designed for enhanced topical delivery of cefixime (CEF-NP) using hydroxypropyl methylcellulose (HPMC K100M) and a QbD-optimized formulation process.</p> Methods <p>A 2³ full factorial design and later Central Composite Design (CCD) optimization studied essential variables of CEF concentration, HPMC K100M concentration, and stirring speed. The risk assessment technique led to the identification of essential process parameters that strengthened the formulation. The process successfully optimized two main outcomes, such as entrapment efficiency (EE) and antibacterial activity (zone of inhibition, ZOI).</p> Results <p>The drug-polymer compatibility as well as uniform spherical particle shape was also confirmed by concerned evaluations. The optimized CEF-NP showed high drug encapsulation efficiency and superior anti-bacterial activity against <i>S. pyogenes</i> compared to pure CEF. Design space analysis and desirability function evaluation succeeded in validating the model after optimization.</p> Conclusion <p>This study aligns with the Sustainable Development Goals (SDGs) by advancing the development of optimized nanocarrier systems aimed at mitigating antimicrobial resistance, while simultaneously incorporating environmentally sustainable waste management practices. The developed CEF-NP formulation, demonstrates potential for the successful fabrication of an effective topical antimicrobial formulation.</p> Graphical Abstract <p></p>