Mitochondria are essential organelles that produce energy substrates required for organismal functions. These organelles contain their own mitochondrial genome (mtDNA), which can accumulate damage and disrupt mitochondrial function. As such, rigorous surveillance by quality control pathways both within cells and across tissues exist to ensure overall organismal health. One such pathways is the mitochondrial unfolded protein response (UPRmt), which is a transcriptional programme that counteracts dysfunction by transcriptionally upregulating genes to promote mitochondrial repair and recovery. Although small non-coding RNAs (sncRNAs) are well-established regulators of gene expression, their roles in systemic mitochondrial stress signalling are yet to be understood. Here, we identify a previously unrecognised role for the germline-localised Piwi-interacting RNA (piRNA; also known as 21U-RNA) pathway in mitochondrial stress response. Using small RNA sequencing, we found that piRNAs respond to both systemic and tissue-specific mitochondrial stress induced by mtDNA damage in the germline and selected somatic tissues. Integration of small RNA and mRNA transcriptomic datasets further revealed that stress-responsive piRNAs exhibit correlated expression changes with predicted mRNA targets, suggesting that mitochondrial stress alters gene expression through the piRNA pathway. Furthermore, loss of piRNA pathway during neuronal mitochondrial stress enhanced UPRmt activation in both cell-autonomous and cell non-autonomous manner, indicating a role for the piRNA pathway in regulating systemic mitochondrial stress signalling. Together, our findings identify the piRNA pathway as a previously unrecognised regulator for organism-wide mitochondrial stress response, suggesting that mitochondrial stress reshapes gene expression through piRNA-mediated regulation to coordinate inter-tissue mitochondrial stress signalling and maintain organismal homeostasis.