In this work, curcumin (CURC)-encapsulating nanoparticles (NPs), made up of an amphiphilic blend of poloxamers and PLGA (PPC NPs) at different polymer concentrations, were prepared by nanoprecipitation. CURC was preliminarily complexed with (2-hydroxypropyl)-β-cyclodextrin (HPβCD) to improve its loading efficiency. The formation of host-guest complexes of CURC with HPβCD (CD-CURC) was confirmed by means of 1HNMR studies and differential scanning calorimetry (DSC). Nanoprecipitation allowed to obtain NPs with a small size (90–120 nm depending on the polymer concentration), a narrow size distribution and stable in water for 30 days at 4 °C and in RPMI-1640 cell culture medium up to 72 h at 37 °C. The in vitro release of CD-CURC, sustained up to 5 days, was governed mainly by a diffusive mechanism. It was also found that the produced NPs were efficiently internalized by mesothelioma cells (MSTO-211H) in the cytoplasmic space, at an extent strongly dependent on NP size and polydispesity index, therefore pointing at the importance of NP preparation method in improving their uptake.