Polymeric nanocapsules (NC) are versatile mixed vesicular nanocarriers, generally containing a lipid core with a polymeric wall. They have been first developed over four decades ago with outstanding applicability in the cosmetic and pharmaceutical fields. Biodegradable polyesters are frequently used in nanocapsule preparation and among them, polylactic acid (PLA) derivatives and copolymers, such as PLGA and amphiphilic block copolymers, are widely used and considered safe for different administration routes. PLA functionalization strategies have been developed to obtain more versatile polymers and to allow the conjugation with bioactive ligands for cell-targeted NC. This review intends to provide steps in the evolution of NC since its first report and the recent literature on PLA-based NC applications. PLA-based polymer synthesis and surface modifications are included, as well as the use of NC as a novel tool for combined treatment, diagnostics, and imaging in one delivery system. Furthermore, the use of NC to carry therapeutic and/or imaging agents for different diseases, mainly cancer, inflammation, and infections is presented and reviewed. Constraints that impair translation to the clinic are discussed to provide safe and reproducible PLA-based nanocapsules on the market. We reviewed the entire period in the literature where the term “nanocapsules” appears for the first time until the present day, selecting original scientific publications and the most relevant patent literature related to PLA-based NC. We presented to readers a historical overview of these Sui generis nanostructures.