Background: Compound dendrobium candidum (CDC) is formulated from Dendrobium candidum and fragrant peony. Preliminary studies have demonstrated that the combination of CDC with conventional antihypertensive medications exhibits significant synergistic effects in lowering blood pressure. The objective of this study was to evaluate the synergistic effect of combining CDC with antihypertensive medications on refractory hypertension in spontaneously hypertensive rats (SHRs) and to elucidate the underlying mechanisms involved. Methods: SHRs were treated with either CDC alone or CDC combined with two or three antihypertensive agents including irbesartan, amlodipine, or terazosin, for a duration of 6 weeks. The alterations in blood pressure, angiotensin II (Ang II), insulin, blood sugar, angiotensin II type I receptor (AT ₁ R), angiotensin II type II receptor (AT ₂ R), insulin receptor, insulin α receptor, and insulin β receptor levels were assessed. Glomerular endothelial cells from refractory SHR were then taken for overexpression and knockdown of AT ₂ R gene and co‐cultured with CDC serum to measure the expression levels of Ang II receptor gene and protein. Results: In comparison to the findings observed in the irbesartan + amlodipine + terazosin (IAT) group, the addition of CDC significantly enhanced antihypertensive efficacy. The rate of achieving blood pressure targets (< 150 mmHg) in SHRs with refractory hypertension increased from 0% to 100%. Treatment with CDC significantly reduced the compensatory increase in AT ₁ R and AT ₂ R levels caused by IAT treatment and showed a significant antihypertensive and synergistic effect. Primary glomerular endothelial cells extracted from SHRs and Wistar rats and treated with 0.5% CDC‐containing serum showed significantly reduced AT ₂ R levels in the AT ₂ R‐overexpression condition. The combination of CDC and antihypertensive drugs was effective in reducing the messenger RNA (mRNA) and protein expression levels of AT ₁ R and AT ₂ R in glomerular endothelial cells. Conclusions: CDC in combination with antihypertensive drugs showed a synergistic effect in controlling refractory hypertension. The mechanism of action may be related to the attenuation of excessive expression of AT ₂ R. This study offers a novel approach for the treatment of clinically resistant hypertension.