Polylactide acid (PLA), as an FDA-approved biomaterial, has been widely applied due to its unique merits, such as its biocompatibility, biodegradability, and piezoelectricity. Numerous utilizations, including sensors, actuators, and bio-application—its most exciting application to promote cell migration, differentiation, growth, and protein–surface interaction—originate from the piezoelectricity effect. Since PLA exhibits piezoelectricity in both crystalline structure and an amorphous state, it is crucial to study it closely to understand the source of such a phenomenon. In this respect, in the current study, we first reviewed the methods promoting piezoelectricity. The present work is a comprehensive review that was conducted to promote the low piezoelectric constant of PLA in numerous procedures. In this respect, its chemistry and structural origins have been explored in detail. Combining any other variables to induce a specific application or to improve any PLA barriers, namely, its hydrophobicity, poor electrical conductivity, or the tuning of its mechanical properties, especially in the application of cardiovascular tissue engineering, is also discussed wherever relevant.