Organisms respond to mitochondrial stress by activating multiple defense pathways, including the mitochondrial unfolded protein response (UPR^mt). However, how UPR^mt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here, we identify CREB-binding protein-1 (CBP-1), the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPR^mt, as well as the mitochondrial stress-induced immune response, with involvement also in the reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of the histone demethylases JMJD-1.2 and JMJD-3.1 and upstream of UPR^mt transcription factors, including ATFS-1, to systematically induce a broad spectrum of UPR^mt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPR^mt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts the UPR^mt in mammalian cells, while forced expression of p300 is sufficient to activate it. These results highlight an evolutionarily conserved mechanism that determines the mitochondrial stress response and promotes health and longevity through CBP/p300.