Carnosine is a natural occurring endogenous dipeptide that was proposed as an anti-aging agent more than 20 years ago. Carnosine can be found at low millimolar concentrations at brain level and different preclinical studies have demonstrated its antioxidant, anti-inflammatory, and anti-aggregation activity with neuroprotective effects in animal models of Alzheimer’s disease (AD). A selective deficit of carnosine has also been linked to cognitive decline in AD. Different clinical studies have been conducted to evaluate the impact of carnosine supplementation against cognitive decline in elderly and AD subjects. We conducted a systematic review with meta-analysis, in accordance with the PRISMA guidelines coupled to the PICOS approach, to investigate the therapeutic potential of carnosine against cognitive decline and depressive symptoms in elderly subjects. We found five studies matching the selection criteria. Carnosine/anserine was administered for 12 weeks at a dose of 1 g/day and improved global cognitive function, whereas no effects were detected on depressive symptoms. These data suggest a preliminary evidence of clinical efficacy of carnosine against cognitive decline both in elderly subjects and mild cognitive impairment (MCI) patients, although larger and long-term clinical studies are needed in MCI patients (with or without depression) to confirm the therapeutic potential of carnosine.