Meloidogyne enterolobii [a.k.a Guava Root Knot Nematode (GRKN)] is an invasive species that has been slowly spreading across the Southeastern United States over the past twenty years. Recent reports of damage caused by this nematode on sweetpotato have raised serious concerns among growers and regulatory agencies because of its high-level of virulence on a wide range of crop varieties that are normally resistant to the endemic root knot nematode species. During recent surveys in South Carolina, we identified multiple isolates of GRKN originating both from field soil, as well as from fresh market sweetpotatoes. These findings in sweetpotato indicate that this clonally propagated crop has the potential to vector the spread of this nematode. Using a GRKN isolate from South Carolina we screened eighty-seven sweetpotato lines from the USDA-GRIN germplasm collections, and successfully identified multiple lines with high levels of resistance to galling and GRKN reproduction. Further screening of this resistant sweetpotato germplasm against additional GRKN isolates identified pathotypic variability, with certain lines providing resistance to only one nematode isolate. Our results provide valuable insight for breeders, farmers, and pathologists who are seeking to manage, monitor, and deploy resistance against GRKN in the field.