Entecavir (Baraclude®) is used daily as a long-term treatment for hepatitis-B virus infections. In this study a sustained injectable biodegradable in-situ implant (ISI) and polymeric nanoparticles (NPs) of Entecavir were prepared using Poly-d,l-lactic-co-glycolic acid (PLGA) polymer and evaluated for their shape, saturation solubility, in-vitro release and in-vivo efficacy. The pharmacokinetic parameters of Entecavir formulations were studied in rats following intramuscular injection, and the data was analyzed using one-way analysis of variance (ANOVA). TEM photographs showed that the ISI had a porous surface after exposure to Sörensen phosphate buffer pH 7.4 for 24 h, and Entecavir loaded NPs had a spherical structure with a smooth surface. The entrapment efficiency of Entecavir NPs was in the range of 47.03–77.84%. The pharmacokinetic studies showed a significant reduction (p < 0.05) in the Cmax from 353.75 for the pure Entecavir to 16.70 and 172.85 ng/ml for the NPs and ISI formulations, respectively. The AUC0-∞ also increased significantly from 211.32 ng/ml.h for pure Entecavir to 1520.64 and 2363.52 ng/ml.h for ISI and NP formulations, respectively. This study showed the feasibility of intramuscular ISI and NP formulations loaded with Entecavir which exhibit sustained release profiles and a promising strategy for the treatment of chronic hepatitis-B.