Nanochitosan (NC) using Andrographis paniculata L leaf extract (APLE) has been successfully modified to increase the encapsulation efficiency of lamivudine (LAM) and follow the in vitro controlled release study. The hydroxy groups derived from flavonoids and polyphenols of APLE play a role to improve the hydrophilicity of NC, resulting in an outstanding LAM encapsulation efficiency of 96.52%. The characterization results using SEM and PSA showed that the LAM loaded APLE-NC nanodrugs were homogeneously distributed with particle diameters of 170–250 nm. In vitro drug release studies showed that LAM-loaded APLE-NC releases 32.52% in phosphate buffer solution (PBS) pH 3.0 for 4 h and 81.57% in PBS pH 7.4 for 24 h. As a result, LAM-loaded APLE-NC presents remarkable encapsulation efficiency and excellent release behavior compared to LAM-loaded NC. Significantly, this work provides new findings on the pivotal role of APLE, which could be potentially employed as a drug carrier of lamivudine with high encapsulation efficiency as well as release in a controlled manner.