It is unclear whether fever suppression in the elderly provides long-term benefits or poses risks due to their distinct immune profiles and body temperature regulation compared to younger individuals. This study aimed to assess the long-term health effects of antipyretic treatment during infections in the elderly. A systematic review was conducted, including studies that compared antipyretic treatment with other drugs, therapies, placebo, or no treatment. PubMed, Embase and Cochrane CENTRAL databases were searched. Primary and secondary outcomes were the onset or worsening of chronic inflammatory diseases, fever reduction, length of hospital stay, patient satisfaction, mortality, laboratory indicators of morbidity, and progression to complications, respectively. Out of 11,481 studies screened, 17 were included (two randomized controlled trials [RCTs], seven observational studies, one case series, and seven case reports). None investigated the primary outcome or patient-reported outcomes. The risk of bias in the included studies ranged from unclear to high. Due to the heterogeneity of the studies, a narrative synthesis was conducted, as meta-analysis was not feasible. Antipyretics showed a significant reduction of fever in RCTs. Five studies reported a significant drop in blood pressure, and one showed significant mortality from antipyretics. Morbidity indicators and length of stay were available only in the studies that reported adverse events. The certainty of evidence, assessed using GRADE, was low to very low for all outcomes. Evidence regarding the long-term benefit or harm from fever suppression with antipyretics during infections in the elderly is insufficient.