Cancers arise through accumulation of genetic and epigenetic alterations allowing cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis, an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and cancer-relevant chromosomal aberrations . However, little is known about the molecular events regulating the onset of this important tumor-suppressive barrier. Here we identified the innate immune sensor ZBP1 (Z-nucleic acid binding protein 1) as a novel regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS/STING DNA-sensing pathway, but only reaches full activation when associated with TERRA (Telomeric repeat-containing RNA) transcripts synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into long filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adaptor protein MAVS (Mitochondrial antiviral-signaling protein). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study establishes a tumor-suppressive mode of telomere-to-mitochondria signaling, whereby dysfunctional telomeres activate lethal innate immune signaling through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.