Exercising at submaximal intensity with a hand dynamometer causes mild hemodynamic adaptations that can improve cardiovascular function. However, hemodynamic responses and fatigue have not been adequately studied in an isometric exercise protocol combined with blood flow restriction (BFR). Our study aimed to examine and compare acute hemodynamic responses and muscle fatigue after an isometric exercise session using a handgrip dynamometer, with and without BFR. Twelve volunteers performed the exercise protocol, with and without BFR, at random, with the BFR pressure set at 140 mmHg. Arterial blood pressure (BP), heart rate (HR), oxygen saturation (SpO2), and muscle fatigue were measured before, during, and 15 min after the completion of the exercise session. Without BFR, we noticed a slight, albeit statistically insignificant, HR increase. The variations found in systolic and diastolic pressure were small and statistically insignificant. Furthermore, blood oxygen saturation (SpO2) did not change significantly. Significantly higher levels of fatigue were found in exercise with BFR, compared to without BFR, at the end of each set of isometric contractions. In conclusion, a handgrip exercise session with mild BFR does not alter the acute hemodynamic responses to exercise in healthy volunteers. However, it results in higher muscle fatigue compared to that experienced after exercise without BFR.