Objective To define the functional mechanisms of two NSAIDs, paracetamol and ibuprofen, in specific brain regions in headache control by observing the distribution of Fos-immunoreactive neurons in trigeminal ganglia and trigeminal nucleus caudalis in conscious rat models of vasculogenic headache. Methods Thirty male Sprague-Dawley rats were randomly divided into three groups: control group (saline group), acetaminophen group and ibuprofen group. Each rat was given electrical stimulation (frequency 20 Hz, current 3-5 mA, pulse width 0.25 ms) at 50 minutes after injection. The rats were killed and perfusion fixed after electrical stimulation. Trigeminal ganglia and trigeminal nucleus caudalis of the brains were taken out for paraffin sections and immunohistochemical staining, and Fos-immunoreactive neurons were counted under the Image J system. Results After electrical stimulation, there were significant differences of Fos protein expression in bilateral trigeminal ganglia and spinal trigeminal nucleus caudalis between the saline group and groups of non-steroidal anti-inflammatory drugs, but no significant difference of Fos protein expression in bilateral trigeminal ganglia and spinal trigeminal nucleus caudalis between the acetaminophen group and ibuprofen group. Conclusions The changes of Fos expression in bilateral trigeminal ganglia and spinal trigeminal nucleus caudalis after treatment with NSAIDs suggest that such structures participate in the pain transmission and expression and the pharmacology course of analgesic drugs.