Background: Cymbopogon caesius (Ness) Stapf. is a traditional Uyghur medicinal material that is used for the treatment of pain, rheumatism, cold, indigestion, and injury. Objective: The aim of this study was to isolate the antihypertensive activity compounds from C. caesius (Ness) Stapf. Materials and Methods: Cymbopogon caesius (Ness) Stapf. was reflux extracted by EtOH, and the obtained extracts were screened for antihypertensive compounds via the hypertension model of rabbits and rats. The hypertensive extracts were separated via column chromatography and recrystallization and screened for antihypertensive compounds by the hypertension model of rats induced by L-NG-nitroarginine (L-NNA). Their structures were elucidated by nuclear magnetic resonance (NMR) spectroscopy and melt point. Results: Three compounds, namely, isoorientin (Compound I), β-sitosterol (Compound II), and chlorogenic acid (Compound III), were isolated from the dried aerial part of C. caesius (Ness) Stapf. via bioactivity-guided fractionation. Their structures were elucidated by NMR spectroscopy and melt point. Isoorientin may reduce the rats' blood pressure, which was elucidated through the diastolic blood pressure and systolic blood pressure of L-NNA-induced hypertensive rat model experiment. Conclusion: Isoorientin is one of the novel compounds of C. caesius (Ness) Stapf. for the treatment of hypertension diseases.