Resistance training with low loads in combination with blood flow restriction (BFR) facilitates increases in muscle size and strength comparable with high-intensity exercise. We investigated the effects of BFR on single motor unit discharge behavior throughout a sustained low-intensity isometric contraction. Ten healthy individuals attended two experimental sessions: one with, the other without, BFR. Motor unit discharge rates from the tibialis anterior (TA) were recorded with intramuscular fine-wire electrodes throughout the duration of a sustained fatigue task. Three 5-s dorsiflexion maximal voluntary contractions (MVC) were performed before and after the fatigue task. Each participant held a target force of 20% MVC until endurance limit. A significant decrease in motor unit discharge rate was observed in both the non-BFR condition (from 13.13 ± 0.87Hz to 11.95 ± 0.43Hz, P = 0.03) and the BFR condition (from 12.95 ± 0.71Hz to 10.9 ± 0.75Hz, P = 0.03). BFR resulted in significantly shorter endurance time and time-to-minimum discharge rates and greater end-stage motor unit variability. Thus, low-load BFR causes an immediate steep decline in motor unit discharge rate that is greater than during contractions performed without BFR. This shortened neuromuscular response of time-to-minimum discharge rate likely contributes to the rapid rate of neuromuscular fatigue observed during BFR.