Parkinson’s disease (PD) is increasingly linked to gut-brain axis dysfunction. While broad-spectrum antibiotics may contribute to gut dysbiosis, which has been associated with an increased abundance of curli-producing Enterobacteriaceae and processes implicated in α-synuclein aggregation, certain antibiotic classes, particularly tetracyclines and β-lactams, have demonstrated neuroprotective properties in pre-clinical models of PD. This creates a therapeutic paradox: antibiotics may exert either beneficial or detrimental effects depending on many factors including host microbiome composition. Importantly, much of the current evidence remains observational or pre-clinical, and a direct causal relationship between antibiotic exposure and PD has not yet been established. This review synthesizes current epidemiological, mechanistic, and pre-clinical evidence regarding this paradox and explores the emerging role of nanotechnology in resolving it. Preclinical studies suggest that nanoparticle-based drug delivery systems may enhance BBB penetration and enable more targeted drug release. Such approaches have been proposed as a means to reduce systemic exposure and potentially limit microbiota disruption, although these benefits have not yet been demonstrated in clinical PD populations. We further discuss the translational hurdles, including nanotoxicity and regulatory requirements, and propose a roadmap for future research that integrates metagenomics with precision nanomedicine. Collectively, these findings provide a framework for future investigation of targeted therapeutic strategies for PD. However, substantial mechanistic, clinical, and translational validation is required before their therapeutic potential can be established.