Background: The presence of oxidative stress, telomere shortening, and apoptosis in polypathological patients (PP) with sarcopenia and frailty remains unknown. Methods: Multicentric prospective observational study in order to assess oxidative stress markers (catalase, glutathione reductase (GR), total antioxidant capacity to reactive oxygen species (TAC-ROS), and superoxide dismutase (SOD)), absolute telomere length (aTL), and apoptosis (DNA fragmentation) in peripheral blood samples of a hospital-based population of PP. Associations of these biomarkers to sarcopenia, frailty, functional status, and 12-month mortality were analyzed. Results: Of the 444 recruited patients, 97 (21.8%), 278 (62.6%), and 80 (18%) were sarcopenic, frail, or both, respectively. Oxidative stress markers (lower TAC-ROS and higher SOD) were significantly enhanced and aTL significantly shortened in patients with sarcopenia, frailty or both syndromes. No evidence of apoptosis was detected in blood leukocytes of any of the patients. Both oxidative stress markers (GR, p = 0.04) and telomere shortening (p = 0.001) were associated to death risk and to less survival days. Conclusions: Oxidative stress markers and telomere length were enhanced and shortened, respectively, in blood samples of polypathological patients with sarcopenia and/or frailty. Both were associated to decreased survival. They could be useful in the clinical practice to assess vulnerable populations with multimorbidity and of potential interest as therapeutic targets.