Enzyme-resistant glucose-dependent insulinotropic polypeptide (GIP) agonists offer therapeutic potential for type 2 diabetes treatment. In addition, there is emerging evidence suggesting that GIP plays a direct role in modulating aspects of brain function. This study compared effects of dietary modification and/or twice-daily injection of the stable GIP agonist, (d-Ala²)GIP, on metabolic control, cognitive function and hippocampal synaptic plasticity in high-fat fed mice. Young Swiss mice were maintained on high-fat diet for 155days, at which point half of the animals were switched to standard maintenance diet. Mice were subsequently injected with (d-Ala²)GIP (25nmol/kg bodyweight; b.i.d.) or saline vehicle for 28days. Both dietary intervention and (d-Ala²)GIP treatment were equally effective in restoring non-fasting glycaemic control (P<0.001) and improving (P<0.05 to P<0.001) glucose tolerance in high-fat fed mice. Switching to standard diet alone or in combination with (d-Ala²)GIP treatment returned body weights of high-fat fed mice to normal levels by day 28. However, body weights of high-fat fed mice treated with (d-Ala²)GIP were not significantly different from controls. (d-Ala²)GIP did not affect food intake or plasma insulin levels irrespective of diet. All mice treated with (d-Ala²)GIP exhibited a marked increase in recognition index (1.4-fold; P<0.05) highlighting improved cognitive function. Furthermore, switching to standard diet and/or (d-Ala²)GIP treatment rescued deleterious effects of high-fat feeding on long-term potentiation of synaptic neurotransmission. These results demonstrate that prolonged GIP activation is equally effective or superior to dietary intervention, in improving glucose intolerance and aspects of cognitive function and hippocampal synaptic plasticity in high-fat fed mice.