Prostate cancer (PCa) is one of the most common cancers in older men and is associated with high mortality. Despite advances in screening for early detection of PCa, a large proportion of patients continue to be diagnosed with metastatic disease, with ~20% of men showing a high tumor grade and stage. Medicinal plant extracts have a great potential to prevent/treat PCa, as well as to reduce its incidence/prevalence and improve survival rates. One of the most promising extracts is curcumin, which is a major, nontoxic, bioactive compound of Curcuma longa. Curcumin has strong antitumor activity in vitro. However, its potential beneficial in vivo affects are limited by its low intestinal absorption and rapid metabolism. In this study, curcumin was impregnated into a biodegradable poly(lactic-co-glycolic) acid (PLGA) support and characterized by FTIR and DSC, and its release by UV spectrophotometry. PLGA-curcumin was tested in different subcutaneous PCa xenograft models (PC3, 22rv1, and DU145 PCa cell-lines), and its effects evaluated by tumor progression an immuno-histochemical analysis (Trichromic, Ki67 and TUNEL stainings), were compared with those of a commercial curcumin preparation. Our results indicate that curcumin-impregnated PLGA is significantly more active (~2-fold increase) with respect to oral curcumin, which supports its use for subcutaneous administration.