This work examined the effects of four plasticizers, glycerol (GLY), potassium phosphate (PHOS), polyethylene glycol (PEG), and soy lecithin (SL), on the structural, surface, thermal, optical, and mechanical properties of polyhydroxybutyrate (PHB) films. FTIR spectra demonstrated that these plasticizers maintained the PHB molecular structure, while X-ray diffraction data proved that PHB crystallinity decreased upon adding SL, GLY, and PHOS. Under SEM, we discovered several defects in the plasticized samples, most of which were holes of distinct sizes and forms. The thermal analyses evaluated the impact of plasticization on PHB thermal processability, demonstrating that the material’s thermal stability improved, easing thermal processing due to the reduced melting peak temperatures (T_m) caused by all the additives assessed. While PEG, GLY, and PHOS reduced the hydrophilicity of the film, SL enhanced its affinity to water, as shown by the contact angle measurements. Reduced transparency resulted from adding 20% plasticizers with an increase of 345% in elongation at break and a decrease of 67% in elastic modulus compared to pristine PHB. Thus, SL proved to be the most promising of the four plasticizers used in terms of mechanical properties, crucial for PHB-based films for food packaging.