Dioxolanes-based nucleosi(t)des are characterized by their unique replacement of sugar moiety by dioxalane-based cyclopentyl rings. These nucleosides have emerged as promising candidates in antiviral and anticancer drug discovery and exhibit substantial antiviral activity against several viruses, including human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Unlike conventional nucleosides, dioxolane nucleos(t)ides lack the 3' OH group essential for DNA/RNA elongation, enabling them to selectively target DNA viruses without causing toxicity to humans. The series of these compounds interrupt viral growth either by hampering the activity of DNA polymerase or by terminating the growing viral DNA chain. Similarly, oxythiolane sugars-based nucleos(t)ides have also demonstrated strong antiviral activity, leading to the approval of therapies for HIV and hepatitis B virus (HBV) infections. Our group has invented 1-{(2S,4S-2-(hydroxymethyl)-1,3-dioxolane-4-yl)5-vinylpyridine-2,4(1H,3H)-dione (L-HDVD) that exhibits broad-spectrum antiviral potency against Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV). A prodrug approach was adopted to improve the antiviral profile, bioavailability, and cellular update of L-HDVD. In this effort, synthesis, and evaluation of numerous L-HDVD prodrugs: phosphoramidate (12), long-chain lipids (ODE-L-HDVD, 21, and HDP-L-HDVD, 22), amino ester (20) and phosphate ester prodrugs (POM-L-HDVD,10, and POC-L-HDVD,18) have been reported. The synthesized prodrugs have been evaluated against EBV and HSV in P3HR-1 cells and by the real-time PCR detection of viral DNA. Against EBV, L-HDVD and POM-L-HDVD (10) expressed the greatest potency with EC50 of 0.12 and 0.16 µM and selectivity index (SI) of 909 and 375, respectively. Phosphoramidate (12) also demonstrated an EC50 value of 1.24 µM activity, which was superior to ganciclovir (EC50 = 2.52 with SI of 37)