Background Chronic obstructive pulmonary disease (COPD) exacerbation (ECOPD) alters the natural course of the disease. To date, only C-reactive protein has been used as a biomarker in ECOPD, but it has important limitations. The mitochondria release peptides (Humanin (HN), FGF-21, GDF-15, MOTS-c and Romo1) under certain metabolic conditions. Here, we aimed to evaluate the pathophysiologic, diagnostic and prognostic value of measuring serum mitochondrial peptides at hospital admission in patients with ECOPD. Methods A total of 51 consecutive patients admitted to our hospital for ECOPD were included and followed for 1 year; in addition, 160 participants with stable COPD from our out-patient clinic were recruited as controls. Results Serum FGF-21 ( p < .001), MOTS-c ( p < .001) and Romo1 ( p = .002) levels were lower, and GDF-15 ( p < .001) levels were higher, in patients with ECOPD than stable COPD, but no differences were found in HN. In receiver operating characteristic analysis, MOTS-c (AUC 0.744, 95% CI 0.679–0.802, p < .001) and GDF-15 (AUC 0.735, 95% CI 0.670–0.793, p < .001) had the best diagnostic power for ECOPD, with a diagnostic accuracy similar to that of C-RP (AUC 0.796 95% IC 0.735–0.848, p < .001). FGF-21 (AUC 0.700, 95% CI 0.633–0.761, p < .001) and Romo1 (AUC 0.645 95% CI 0.573–0.712, p = .001) had lower diagnostic accuracy. HN levels did not differentiate patients with ECOPD versus stable COPD ( p = .557). In Cox regression analysis, HN (HR 2.661, CI95% 1.009–7.016, p = .048) and MOTS-c (HR 3.441, CI95% 1.252–9.297, p = .016) levels exceeding mean levels were independent risk factors for re-admission. Conclusions Most mitochondrial peptides are altered in ECOPD, as compared with stable COPD. MOTS-c and GDF15 levels have a diagnostic accuracy similar to C-RP for ECOPD. HN and MOTS-c independently predict future re-hospitalization.