In this study, the coordinated activation of ubiquitin-proteasome pathway (UPP), autophagy-lysosomal pathway (ALP), and mitochondrial remodeling including mitophagy was assessed by measuring protein markers during ultra-endurance running exercise in human skeletal muscle. Eleven male, experienced ultra-endurance athletes ran for 24 h on a treadmill. Muscle biopsy samples were taken from the vastus lateralis muscle 2 h before starting and immediately after finishing exercise. Athletes ran 149.8 ± 16.3 km with an effective running time of 18 h 42 min (±41min). The phosphorylation state of Akt (−74 ± 5%; P < 0.001), FOXO3a (−49 ± 9%; P < 0.001), mTOR Ser2448 (−32 ± 14%; P = 0.028), and 4E-BP1 (−34 ± 7%; P < 0.001) was decreased, whereas AMPK phosphorylation state increased by 247 ± 170% (P = 0.042). Proteasome β2 subunit activity increased by 95 ± 44% (P = 0.028), wheras the activities associated with the β1 and β5 subunits remained unchanged. MuRF1 protein level increased by 55 ± 26% (P = 0.034), whereas MAFbx protein and ubiquitin-conjugated protein levels did not change. LC3bII increased by 554 ± 256% (P = 0.005), and the form of ATG12 conjugated to ATG5 increased by 36 ± 17% (P = 0.042). The mitochondrial fission marker phospho-DRP1 increased by 110 ± 47% (P = 0.003), whereas the fusion marker Mfn1 and the mitophagy markers Parkin and PINK1 remained unchanged. These results fit well with a coordinated regulation of ALP and UPP triggered by FOXO3 and AMPK during ultra-endurance exercise.