Spasticity is one of the most physically debilitating disabilities following stroke and may slow down the potential success of rehabilitation. Glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been shown to play a crucial role in spasticity following cerebral ischemia/reperfusion (I/R) injury. Gua Lou Gui Zhi decoction (GLGZD) is a well-known traditional Chinese formula that has long been used clinically in China to treat muscular spasticity following stroke, epilepsy or spinal cord injury. However, the precise mechanisms behind its neuroprotective and anti-spasticity effects remain poorly understood. In the present study, using a rat model of focal cerebral I/R injury, we evaluated the neuroprotective and anti-spasticity effects of GLGZD and investigated the underlying mechanisms. We found that GLGZD improved neurological deficits and reduced infarct volumes in cerebral I/R-injured rats. In addition, GLGZD reduced cerebral ischemic spasticity since it improved the screen test and Hoffman's reflex (H-reflex) scores. It also reduced glutamate levels in the cerebrospinal fluid and altered the expression of the AMPA receptor subunits. Our data demonstrate that GLGZD exerts neuroprotective and anti-spasticity effects in a cerebral ischemia model via the modulation of glutamate levels and AMPA receptor expression.