Background: Neurodegenerative disorders (such as Alzheimer disease) characterized by the deposition of various pathogenic forms of tau protein in the brain are collectively referred to as tauopathies. Identification of the molecular drivers and pathways of neurodegeneration is critical to individualized targeted treatment of these disorders. However, despite important advances in fluid biomarker detection, characterization of these molecular subtypes is limited by the blood-brain barrier. Purpose: To evaluate the feasibility and safety of focused ultrasound–mediated liquid biopsy (sonobiopsy) in the detection of brain-derived protein biomarkers in a transgenic mouse model of tauopathy (PS19 mice). Materials and Methods: Sonobiopsy was performed by sonicating the cerebral hemisphere in 2-month-old PS19 and wild-type mice, followed by measurement of plasma phosphorylated tau (p-tau) species (30 minutes after sonication in the sonobiopsy group). Next, spatially targeted sonobiopsy was performed by sonicating either the cerebral cortex or the hippocampus in 6-month-old PS19 mice. To detect changes in plasma neurofilament light chain (a biomarker of neurodegeneration) levels, blood samples were collected before and after sonication (15 and 45–60 minutes after sonication). Histologic staining was performed to evaluate tissue damage after sonobiopsy. The Shapiro-Wilk test, unpaired and paired t tests, and the Mann-Whitney U test were used. Results: In the 2-month-old mice, sonobiopsy significantly increased the normalized levels of plasma p-tau species compared with the conventional blood-based liquid biopsy (p-tau-181–to–mouse tau [m-tau] ratio: 1.7-fold increase, P = .006; p-tau-231–to–m-tau ratio: 1.4-fold increase, P = .048). In the 6-month-old PS19 mice, spatially targeted sonobiopsy resulted in a 2.3-fold increase in plasma neurofilament light chain after sonication of the hippocampus and cerebral cortex (P < .001). After optimization of the sonobiopsy parameters, no excess microhemorrhage was observed in the treated cerebral hemisphere compared with the contralateral side. Conclusion: This study showed the feasibility of sonobiopsy to release phosphorylated tau species and neurofilament light chain to the blood circulation, potentially facilitating diagnosis of neurodegenerative disorders.