Cellular stressors often cause widespread repression of RNA polymerase II (RNAP II) activity, which is thought to facilitate a focused transcriptional output towards stress resolution. In many cases, however, the underlying regulatory mechanisms remain unknown. Here, we demonstrate that stress-induced downregulation of the general transcription factor TFIIB tunes the expression of specific stress response genes. In response to a variety of stressors, TFIIB is proteolytically cleaved at a conserved aspartic acid residue by caspases 3 and 7. Using both overexpression and endogenous base-editing, we find that B and T cells that are unable to cleave TFIIB fail to appropriately dampen transcription of short, stimulus-responsive and proto-oncogenic genes. The promoters of TFIIB-sensitive genes are bound by TFIIB and RNAP II, although their transcription is restrained until stimulated by stress. Subsequently, their expression is modulated through TFIIB cleavage. We further demonstrate that stress-induced TFIIB cleavage prevents aberrant lymphocyte proliferation and suppresses transcription from a pathogenic gammaherpesvirus. Hence, caspase targeting of TFIIB destabilizes transcription to tune gene expression, allowing for proper stress resolution.