The Wnt/${eta}$-catenin pathway plays important roles in a variety of biological processes, such as cell proliferation, differentiation, and organ development. Here, we used a cell-based reporter assay to identify bryostatin-1, a natural macrocyclic lactone, as an inhibitor of the Wnt/${eta}$-catenin pathway. Bryostatin-1 suppressed ${eta}$-catenin response transcription (CRT), which was activated by a Wnt3a-conditioned medium (Wnt3a-CM), through a decrease in the intracellular ${eta}$-catenin protein levels, without affecting its mRNA level. In addition, pharmacological inhibition of proteasome abrogated bryostatin-1-mediated down-regulation of the ${eta}$-catenin protein level. Our findings suggest that bryostatin-1 attenuates the Wnt/${eta}$-catenin pathway through the promotion of proteasomal degradation of ${eta}$-catenin.