RING finger 43 (RNF43), a RING‐type E3 ubiquitin ligase, is a key regulator of WNT signaling and is mutated in 6–10% of pancreatic tumors. However, RNF43‐mediated effects remain unclear, as only a few in vivo substrates of RNF43 are identified. Here, it is found that RNF43‐mutated pancreatic cancer cells exhibit elevated B‐RAF/MEK activity and are highly sensitive to MEK inhibitors. The depletion of RNF43 in normal pancreatic ductal cells also enhances MEK activation, suggesting that it is a physiologically regulated process. It is confirmed that RNF43 ubiquitinates B‐RAF at K499 to promote proteasome‐dependent degradation, resulting in reduced MEK activity and proliferative ability in cancer cells. In addition, phosphorylation of B‐RAF at T491 suppresses B‐RAF ubiquitination by decreasing the interaction between RNF43 and B‐RAF. Mutations at K499 in B‐RAF are identified in various cancer types. MEK and WNT inhibitors synergistically suppress the growth of RNF43‐mutated pancreatic cancer cells in vitro and in vivo. Collectively, the research reveals a novel mechanism by which RNF43 inhibits B‐RAF/MEK signaling to suppress tumor growth and provide a new strategy for the treatment of RNF43‐inactivated pancreatic cancer. It is demonstrated that RNF43 ubiquitinates B‐RAF at K499, promoting its degradation. This ubiquitination process is negatively regulated by phosphorylation at T491. Inactivation of RNF43 enhances sensitivity to MEK inhibitors and creates synergy between drugs targeting the WNT and MEK pathways in various RNF43‐mutated cancers.