Poly-ɛ-caprolactone nanocapsules loading cloxacillin benzathine (CLOXB-NC) were produced by batch-nanoprecipitation (BNP) and millifluidic continuous flow (CNP) methods. Regarding the CNP, a new millifluidics device was constructed, and the effects of flow rate and organic to aqueous phase proportions (OP/AP) were investigated. Dynamic light scattering (DLS) and atomic force microscopy (AFM) were used to characterize the NC size distribution and morphology, respectively. CLOXB was quantified by high-performance liquid chromatography (HPLC) to determine encapsulation efficiency (EE) and loading yield. DLS results show that unloaded NC can be produced with a narrow size distribution by CNP with an AP flow of 77 mL/min with an OP/AP of 1:2 by CNP. Based on optimized conditions, CLOXB-NC was produced and compared with the BNP method. CLOXB-NC produced by CNP was spherical and presented a higher EE and a smaller distribution size than NC produced by BNP. Freeze-drying was carried out under two freezing conditions, −20 °C and fast frozen in liquid nitrogen (−196 °C). DLS, HPLC, AFM, SEM, and thermal analysis were applied to characterize the freeze-dried formulations. Both freezing conditions were satisfactory for producing CLOXB-NC powders using sucrose as a cryoprotectant. After powder resuspension, CLOXB-NCs frozen in liquid nitrogen showed superior drug leakage than samples frozen at −20 °C. Interestingly, CLOXB-NCs produced by CNP tolerated the freeze-drying process better. NC loading CLOXB (0.5 mg/mL) produced by CNP and frozen at −20 °C with 10 % (p/v) of sucrose demonstrated Sf/Si closest to 1, less drug leakage, fluffy and porous cake. In conclusion, this novel approach to producing NC in continuous flow in a simple and accessible millifluidic device represents an innovative process to improve NC's aptness to withstand mechanical stress during the freeze-drying process.