Programmed death ligand 1 (PD‐L1) is critical for the ability of cancer cells to evade attacks by the host immune system. However, the molecular mechanisms controlling PD‐L1 expression have not been fully understood. Here, we demonstrate that sorting nexin 6 (SNX6) is a novel regulator of PD‐L1 expression. Knockdown of SNX6 in cancer cells significantly decreases PD‐L1 protein levels. In contrast, loss of SNX6 does not reduce PD‐L1 mRNA levels. Instead, SNX6 interacts with Cullin3, an E3 ubiquitin ligase responsible for PD‐L1 ubiquitination and subsequent degradation. By binding with Cullin3, SNX6 decreases the interaction between the adaptor protein speckle‐type POZ protein and Cullin3, which in turn downregulates Cullin3‐mediated PD‐L1 ubiquitination. This research reveals a novel molecular nexus in modulating PD‐L1.