This paper aimed to examine the acute effect of low-load (LL) exercise with blood-flow restriction (LL-BFR) on microvascular oxygenation and muscle excitability of the vastus medialis (VM) and vastus lateralis (VL) muscles during a single bout of unilateral knee extension exercise performed to task failure. Seventeen healthy recreationally resistance-trained males were enrolled in a within-group randomized cross-over study design. Participants performed one set of unilateral knee extensions at 20% of one-repetition maximum (1RM) to task failure, using a LL-BFR or LL free-flow (LL-FF) protocol in a randomized order on separate days. Changes in oxygenation and muscle excitability in VL and VM were assessed using near-infrared spectroscopy (NIRS) and surface electromyography (sEMG), respectively. Pain measures were collected using the visual analog scale (VAS) before and following set completion. Within- and between- protocol comparisons were performed at multiple time points of set completion for each muscle. During LL-BFR, participants performed 43% fewer repetitions and reported feeling more pain compared to LL-FF (p<0.05). Normalized to time to task failure, LL-BFR and LL-FF generally demonstrated similar progression in microvascular oxygenation and muscle excitability during exercise to task failure. The present results demonstrate that LL-BFR accelerates time to task failure, compared with LL-FF, resulting in a lower dose of mechanical work to elicit similar levels of oxygenation, blood-pooling, and muscle excitability. LL-BFR may be preferable to LL-FF in clinical settings where high workloads are contraindicated, although increased pain experienced during BFR may limit its application.