Effects of Lepidium sativum and Curcuma longa were investigated on pharmacokinetics and pharmacodynamics of antihypertensive drug (amlodipine). Hypertensive rats were treated with amlodipine, Lepidium sativum, Lepidium sativum + amlodipine, Curcuma longa and Curcuma longa + amlodipine, and their blood pressures were measured. Amlodipine in plasma samples was analysed using UPLC-TQD. Product ions of amlodipine were monitored at m/z 409.18 > 238 and 409.18 > 294, and of nitrendipine at m/z 361.16 > 315.1 and 361.16 > 329.10. Lepidium sativum + amlodipine treatment showed highest reduction in systolic blood pressure (SBP). Mean anti-hypertensive effect of Lepidium sativum and Curcuma longa was similar to amlodipine. Mean SBPs (1–24 h) of amlodipine, Lepidium sativum, Lepidium sativum + amlodipine, Curcuma longa and Curcuma longa + amlodipine-treated animals were found as 149.5 ± 2.4 mmHg, 151.6 ± 1.09 mmHg and 141.8 ± 2.5 mmHg, 154.9 ± 2.2 mmHg and 144.4 ± 2.6 mmHg (p-value ≤0.05), respectively. Lepidium sativum and Curcuma longa significantly increased amlodipine Cmax by 83% (p-value 0.018) and 53% (p-value 0.035), and AUC0–t by 48% (p-value >0.05) and 56% (p-value 0.033), respectively. Results of pharmacokinetic and pharmacodynamic studies are in agreement. Lepidium sativum and Curcuma longa augment antihypertensive effect of amlodipine, which is also supported by pharmacokinetic observations.