Melanoma is an aggressive and drug-resistant cancer in need of improved therapeutic strategies. Restored expression of transcriptionally silenced genes is a potential approach, but it is limited by the genetic diversity of the melanoma tumors. The atypical heat shock protein H11/HspB8 has kinase activity and is silenced in melanoma through aberrant DNA methylation. We report that its restored expression induces the death of genetically diverse melanoma lines and inhibits tumor growth through the activation of novel TAK1-dependent death pathways. These include (i) caspase-1 activation independent of the inflammasome through upregulation of apoptosis-associated speck-like protein containing a CARD (ASC), (ii) Beclin-1 upregulation through phosphorylation of mammalian target of rapamycin (mTOR) at S2481 and (iii) apoptosis caused by caspase-1-mediated Beclin-1 cleavage. These data extend current understanding of cell death-associated functions, underscore the strong therapeutic promise of H11/HspB8 and identify TAK1 as a potential intervention target in melanoma.