The objective of this study was to investigate the activation of natural killer (NK) cells and anticancer effects of exo-biopolymer from rice bran cultured with Lentinus edodes [rice bran exo-biopolymer (RBEP)]. Oral administration of RBEP induced the activation of NK cells in a dose-dependent manner. RBEP also prolonged the life spans of mice transplanted with Sarcoma-180 cells and inhibited growing Sarcoma-180 cells in intraperitoneum. Solid tumor growth was also suppressed by oral administration of RBEP in C57/Bl6 mice transplanted with B16/Bl6 melanoma. Intraperitoneal injection of RBEP was more effective than oral administration at the same dosage in mice with transplanted tumor cells. According to this result, when RBEP directly contacts immune cells, the anticancer activity is higher than by indirectly inducing an immune response through oral administration. Therefore, we suggest that the administration of RBEP may be effective for preventing and/or treating cancer through NK cell activation. However, further studies are needed to elucidate the possible mechanisms of the anticancer activity and to investigate the other beneficial effects of RBEP for the development of a new biological response modifier.