Background and Purpose: PD-1 and PD-L1 antibodies have brought extraordinary clinical beneficial for cancer patients and their indications are expanding incessantly. Currently, most PD-1/PD-L1 products are delivered intravenously which may be inconvenient for some cancer patients. Here, we developed a novel oral delivered small molecular, YPD-29B, which targeted human PD-L1 specifically. Experimental Approach: HTRF and SPR assay were used to detect the binding affinity of YPD-29B and PD-L1. The PD-L1 dimerization were proved by native page and HTRF. PD-L1 cell based assay and PBMC cell activation assay were conducted to detect the T cell activation by YPD-29B in vitro. And human PD-1 humanized mice were used to test the antitumor activity and tolerance of YPD-29B in vivo. Key Results:: Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. Moreover, YPD-29B exhibited great antitumor activity and was well tolerated in vivo. Conclusion and Implications: Our results indicated that YPD-29B serves as a promising therapeutic anti-human PD-L1 candidate for cancer immunotherapy.