Colon cancer is the third most frequent neoplasm and the second most lethal worldwide. Despite progress in its treatment, new therapies are still needed to improve the prognosis of this type of tumor and, in this context, the use of plant compounds with anti-tumor properties has been increasing in recent years. The aim of this systematic review was to analyze the potential benefits of encapsulation of compounds derived from plant extracts in nanoparticles and their cytotoxic effect under in vitro conditions. Once the search strategy was defined based on the selected MESH terms, 147 publications published since 2012 were identified from three different databases (PubMed, SCOPUS and WOS). After eliminating duplicates and applying the inclusion and exclusion criteria, 17 studies were finally included. The results showed that the use of natural extracts encapsulated in nanoparticles offered significant cytotoxic activity against colon neoplastic cells by increasing the therapeutic effect of free plant extracts through their encapsulation and without producing toxicity on healthy cells. In addition, most studies (14) involved metal-derived nanoparticles (zinc, iron and gold). Despite the possible efficacy of these nanodrugs, more in vivo studies are needed to elucidate their potential future therapeutic application and their biocompatibility.