Background: Infections are common in patients with advanced illnesses for whom the intravenous or oral route is not possible. The subcutaneous administration of antibiotics is a promising alternative, but there is not enough theoretical support for its use. This study aims to explore the effectiveness and safety of subcutaneous antibiotic therapy in the context of palliative care in elderly patients. Methods: A systematic review was conducted using PubMed and Embase, without time or language limits. Seven articles were selected on the effectiveness of subcutaneous antibiotic therapy in adult patients with chronic progressive diseases. The quality of the articles was assessed with the Newcastle Ottawa Scale and relevant data was extracted using a selection capture file. Results: Seven quasi-experimental studies evaluated 865 elderly patients with advanced diseases, comorbidities, and infections (ie, urinary tract, respiratory system, and bone joint) who received subcutaneous antibiotic therapy (ie, Ceftriaxone, Ertapenem, and Teicoplanin). The pooled success rate of subcutaneous antibiotics for the 7 studies was 71%, the therapy failure rate was 22%, its withdrawal mean was 8%, and the mean mortality rate was 7%. The studies were of low quality and were heterogeneous in the types of infections, types of antibiotics, time of follow-up, and outcomes assessed. Conclusions: Pilot studies have found a limited number of antibiotics that can be safely used to treat specific infections. Nevertheless, the data isn´t robust enough to recommend their use.