Poly(lactic acid) (PLA) is characterized by unique features, e.g., it is environmentally friendly, biocompatible, has good thermomechanical properties, and is readily available and biodegradable. Due to the increasing pollution of the environment, PLA is a promising alternative that can potentially replace petroleum-derived polymers. Different biodegradable polymers have numerous biomedical applications and are used as packaging materials. Because the pure form of PLA is delicate, brittle, and is characterized by a slow degradation rate and a low thermal resistance and crystallization rate, these disadvantages limit the range of applications of this polymer. However, the properties of PLA can be improved by chemical or physical modification, e.g., with biomolecules. The subject of this review is the modification of PLA properties with three classes of biomolecules: polysaccharides, proteins, and nucleic acids. A quite extensive description of the most promising strategies leading to improvement of the bioactivity of PLA, through modification with these biomolecules, is presented in this review. Thus, this article deals mainly with a presentation of the major developments and research results concerning PLA-based materials modified with different biomolecules (described in the world literature during the last decades), with a focus on such methods as blending, copolymerization, or composites fabrication. The biomedical and unique biological applications of PLA-based materials, especially modified with polysaccharides and proteins, are reviewed, taking into account the growing interest and great practical potential of these new biodegradable biomaterials.