ProTide technology, a phosphoramidate-based prodrug strategy, has significantly advanced drug design by enhancing the delivery and activation of nucleoside analogues. By chemically masking the phosphate group, ProTides improve cellular uptake, bypass rate-limiting phosphorylation steps, and enable efficient intracellular release of active monophosphates. This review highlights the structural modifications, mechanistic pathways, and clinical translation of ProTides in antiviral and anticancer therapies. Key FDA-approved drugs such as sofosbuvir, remdesivir, and tenofovir alafenamide demonstrate the success of this approach in overcoming drug resistance, improving bioavailability, and reducing toxicity. Mechanistic insights reveal how esterases and phosphoramidases mediate selective cleavage, releasing the active drug within target cells. Additionally, synthetic strategies for ProTides, including Methods A and B, offer scalable solutions for clinical development. The integration of ProTide chemistry into modern drug discovery exemplifies its transformative role in pharmacology and its potential to address current challenges in therapeutic efficacy and safety.