Glial-fibrillary-acidic-protein (GFAP) has been recently discovered as a biomarker for brain-related pathologies. Severe and mild traumatic injuries, intracerebral hemorrhage and glioblastoma multiforme cancer are all addressable with this circulating biomarker. The aim of this work is to detect GFAP with the best achievable limit of detection by means of an ultra-sensitive surface-acoustic-wave (SAW) based lab-on-a-chip (L oC), which we recently demonstrated. First, we develop several detection strategies by means of gold quartz-crystal-microbalance (QCM) sensors. A polyethylene glycol (PEG) chain is used for antifouling, protein-G for antibody-orientation, and antibody-splitting protocol for high-surface coverage. Then, we exploit the best-performing functionalization for the detection of GFAP with our ultra-high-frequency (UHF) SAW-based L oC. This SAW-L oC can be further developed and engineered with the aim of realizing a point-of-care biosensing platform for the detection of multiple brain-pathology biomarkers.