A series of 2'-deoxy carbocyclic nucleosides characterized by various 6'-substitutions were synthesized and evaluated for their antiviral activities against three viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), and influenza virus. The in vitro antiviral assays indicated that these nucleosides only showed inhibitory activities against HBV, and the substituted groups at the 6' position significantly affected the activity. Among them, the guanosine analog 2b bearing a 6'-α-hydroxyl methyl group was the most potent compound with an EC50 value of 80 nM. The present study provided useful information for the discovery of antiviral carbocyclic nucleosides.