Background: During the COVID-19 pandemic, most of the surgical units involved in the treatment of skin cancers could continue their activities, but the reevaluation of cases and the adaptation of the surgical approach, to limit access and hospital stays, proved to be mandatory. The study aims to demonstrate how the electrochemotherapy (ECT) approach guarantees a chance to keep on delivering comprehensive oncologic surgical treatment in a difficult and high-risk cohort of patients. Methods: We collected 35 elderly and frail patients affected by advanced and metastatic skin cancer who were unsuitable for a standard surgical approach. They were submitted to an ECT protocol, while evaluating the impact of ECT on health-related quality of life, using the EuroQol–five dimensions–three levels (EQ-5D-3L) instrument at baseline and after treatment. Results: A general improvement in health status was reported from the preoperative (mean 56.9) to the postoperative period (mean 63.7), according to the EuroQol–visual analog scale measure. The EuroQol–five dimensions descriptive system showed a reduction of the “patients reporting problems” from the baseline, in the domains for self-care (−27%), usual activities (−24%), pain/discomfort (−43%), and anxiety/depression (−11%). Conclusions: Rapid intervention, minimum hospitalization, palliation in selected cases, and postoperative management with telemedicine may represent the only option in the hands of a surgeon to treat advanced oncologic lesions in fragile patients, especially in a pandemic scenario. ECT can be considered a safe and effective procedure, well tolerated by most elderly and “high-risk” patients.