This paper is aimed to study the plasticizing effectiveness towards poly(lactic acid) (PLA), of innovative and bio-based plasticizers obtained by chemical modification of cardanol. The cardanol derivatives used as PLA plasticizers are raw cardanol, cardanol acetate (CA), and epoxidated cardanol acetate (ECA). The plasticizing performances of cardanol derivatives were compared to those of poly(ethylene glycol) (PEG 400). Plasticized PLA samples were obtained at different amounts of plasticizers, ranging between 10 and 30%. DSC analysis results indicate that addition of cardanol, cardanol acetate and PEG400 involves an initial decrease of the glass transition of the polymer, which however is not substantially modified upon further addition of plasticizer; in contrast, the glass transition continuously decreases upon addition of ECA, which indicates its excellent compatibility with PLA. As a consequence, the glass transition of PLA plasticized by ECA can be reduced well below room temperature. In addition, the presence of the plasticizer increases the crystallization kinetics of PLA, leading to a semi-crystalline structure also at very high cooling rates. Mechanical characterization showed that addition of PEG400, cardanol and CA involves a decrease of the tensile modulus, which is in agreement with the concept of plasticization, and reduction of the glass transition temperature. On the other hand, the increased crystallinity of the material is responsible for a reduction of the elongation at break; in every case, and for any amount of plasticizer, the elongation at break of plasticized PLA is lower than that of neat PLA. Therefore, these materials cannot act as efficient plasticizers for PLA. In contrast, ECA plasticized PLA shows a continuous reduction of the modulus (from 1800 to 3 MPa) and increase of the elongation at break (from 3 to 400%) indicating the excellent plasticizing effectiveness of ECA.