Cardiovascular responses to single stressors diminish over time. Interaction of different stressors influencing hemodynamic variables, indicative of stress-induced reactivity and physiological responses are, however, poorly understood. We investigated time course of mental (using mental arithmetic, MA) and orthostatic (using head up tilt, HUT) challenges induced responses in 16 males. Three protocols were used: HUT, MA and MA + HUT, with sessions randomized and two weeks apart. Hemodynamic responses were compared for 30 s epochs of stress application (stress T1 , stress T2 …). Compared to baseline, HUT, HUT + MA and MA applications affected heart rate (HR) (+ 15.1 ± 8.0 bpm, + 20.0 ± 9.2 bpm, + 11.9 ± 7.2 bpm, all p's b .001, respectively) and stroke volume (SV) (− 22.3 ± 8.1 ml, − 22.0 ± 10.4 ml, − 7.6 ± 8.7 ml, all p's b .001, respectively). HUT and MA + HUT induced HR increases were higher in stress T2 compared to stress T1 (p b .05) and reached maximum at stress T2 . HUT and MA + HUT further reduced SV in stress T2 as compared to stress T1 (p b .001); lowest SV was in stress T2 . Mean arterial pressure reached its minimum in stress T1 during HUT and MA + HUT (− 6.0 ± 8.5 mm Hg, p b .001, − 4.4 ± 9.7 mm Hg, p b .01, respectively) but increased in MA (+ 4.3 ± 3.7 mm Hg, p b .01). Combination of MA + HUT resulted in different time courses of blood pressure responses as compared to HUT alone. We conclude that application of single or combined stress challenges lead to stressor-and time dependent-initial changes in cardiovascular responses. Our findings provide novel insights regarding the duration a stressor must be applied to elicit maximal cardiovascular responses.