Deposition of β‐amyloid (Aβ) peptide is a defining pathological hallmark of Alzheimer's disease (AD) and is involved in memory impairment. Evidence suggests that activation of an extracellular signal‐regulated kinase (ERK) pathway is related to Aβ accumulation. Thus, the aim of the present study was to investigate the effects of an ERK inhibitor (U0126) on amyloidogenesis and cognitive function in Tg2576 mice. Tg2576 mice received injection of U0126 (20 mg/kg, i.p.) or vehicle (1% dimethyl sulfoxide in sterile saline) once a day for 7 days and then cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, immunostainings, western blots, Enzyme‐linked immunosorbent assay (ELISA) and enzyme activity assay were employed to examine a degree of Aβ deposition in the brains. Our results showed that U0126 attenuated memory impairment and inhibited Aβ deposition in the brains of Tg2576 mice. Further experiments revealed that the inhibition of Aβ deposition by U0126 was due to a reduction in β‐secretase and amyloid precursor protein expression in the brains of U0126‐treated Tg2576 mice. These results suggest that the ERK pathway is associated with Aβ accumulation and consequent memory dysfunction in Tg2576 mice and that inhibition of the ERK pathway may be an appropriate intervention in the treatment of AD © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd