One major barrier inhibiting most pharmaceutical administrations' effectiveness is the cellular membrane's insufficient permeability. Cell-penetrating peptides (CPPs) are extensively identified as effective biological carriers that can pass through this natural barrier and transport the CPPs-conjugated therapeutic agents into cells. In this line, CPPs-assisted delivery systems have become one of the most popular methods for internalizing nanoparticles (NPs). Recently, CPPs-functionalized PLGA-derived nanocarriers have attracted exceptional attention because of their distinctive features that make them highly appealing for use in next-generation drug delivery systems (DDS). CPPs-conjugated PLGA NPs have demonstrated promise as therapeutic agents in a range of medical fields. This review article summarizes the current development of the CPPs/PLGA nanocarriers. After that, we explore their various challenges and optimization techniques. Finally, future prospects and challenges of CPPs/PLGA nanocarriers are mentioned concisely.