In this study, digoxin (DG)-loaded solid lipid nanoparticles (DG-SLNs) were successfully prepared by an ultrasonic and high pressure homogenization method. The particle size and distribution, drug loading capacity, drug entrapment efficiency (EE %), zeta potential, and long-term physical stability of the SLNs were characterized in detail. A pharmacokinetic study was conducted in rabbits after oral administration of 0.25 mg DG in different SLNs and it was found that the relative bioavailability of DG in the SLNs was significantly increased compared with that of a DG solution. The addition of CMC-Na in SLNs also markedly increased the oral absorption of DG. These results indicate that DG absorption is enhanced significantly by employing SLN formulations and SLNs are a potential as an oral delivery carrier for poorly water soluble drugs.