Aldo-keto reductase (AKR) 1C isoforms (AKR1C1-C4) are involved in metabolism of steroid hormones, and are targets for treatment of hormone-dependent cancers, such as breast and prostate cancers; as well as hormone-independent leukemias. AKR1C enzymes also metabolize several chemotherapeutics, reducing their effectiveness. Natural products provide a potent source of compounds with anticancer activities. Over 50% of small-molecule anticancer drugs approved by the U.S. FDA are derived from natural products. Previous studies suggest that AKR1C homologs are inhibited by triterpenoids; and we have shown that a pentacyclic steroid derivative is an inhibitor of human AKR1C3. In the present study, a virtual library of 1228 natural products was screened in silico, for relative binding affinity for AKR1C2. Virtual screening was conducted using MTiOpenScreen. The structure of AKR1C2 in complex with ursodeoxycholate was used as ‘receptor’. Results from virtual screening were analyzed in PyMol and validated by comparison with X-ray crystallographic and experimental data. Pentacyclic triterpenoid derivatives with similarities to maslinic, oleaonic, ursolic and betulinic acid were identified among the top 1% of compounds. Several compounds are predicted to form hydrogen bonds with catalytic residues in AKR1C. Oleaonic acid derivatives were shown to inhibit another member of the AKR superfamily, AKR1B10, in vitro. Compounds with similarities to AKR1C inhibitors, such as naringenin and apigenin were ranked among the top 10%. Pentacyclic triterpenoid derivatives have potential anticancer properties, and based on the present study represent a new class of compounds for testing as AKR1C inhibitors.