Personalized antibiotic therapy is transforming infectious disease management by tailoring antimicrobial regimens to individual patient and pathogen characteristics. Unlike conventional one-size-fits-all approaches, personalized strategies integrate host genetic profiles, pharmacokinetics/pharmacodynamics (PK/PD), microbial susceptibility, and biomarker data to optimize therapeutic outcomes while minimizing adverse effects and antimicrobial resistance (AMR). Conventional antibiotic administration often relies on empirical prescribing and fixed dosing, resulting in suboptimal exposure, treatment failures, and selection of resistant strains. Advanced drug delivery systems, including nanocarriers, liposomes, polymeric micelles, and stimulus-responsive platforms, enhance site-specific targeting, controlled release, biofilm penetration, and intracellular delivery, improving antibiotic efficacy and safety. Biomarker-guided selection and PK/PD-informed adaptive dosing allow dynamic adjustments based on infection progression and individual patient responses. Clinical studies demonstrate that these approaches reduce hospital stays, lower treatment failures, and minimize systemic toxicity. Future directions focus on integrating smart delivery systems, biosensors, artificial intelligence, and genomic/microbiome analyses to guide individualized therapy, enabling rapid, precise, and responsive antibiotic administration. Gene-targeted strategies, such as CRISPR-based antimicrobial payloads, offer additional potential to directly disrupt resistance mechanisms. Collectively, these innovations represent a shift toward precision antimicrobial therapy, addressing the limitations of conventional regimens, improving patient-centered outcomes, and mitigating the global AMR crisis.