Purpose To examine muscle oxygenation during running with and without blood flow restriction (BFR). Methods Fifteen aerobically trained males randomly completed four, three-minute running bouts at 70%BFR, 80%BFR, and 90%BFR of their top speed with BFR and 100%NOBFR of their top speed without BFR. Oxygenated hemoglobin (O2Hb), deoxygenated Hb (HHb), total Hb (tHb), Hb difference (HbDiff) and muscle tissue oxygenation (StO2) were assessed continuously throughout the running bouts. Separate two-way, 4 (Intensity [70%BFR, 80%BFR, 90%BFR, 100%NOBFR]) × 3 (Time [120, 150, and 180 s]), repeated-measure ANOVA models were constructed to examine O2Hb, HHb, tHb, HbDiff, and StO2 responses. Results O2Hb decreased (120- [65.25 ± 6.58%] textgreater 150-s [63.72 ± 6.75%]), while HHb increased (120- [14.4 ± 12.55%] textless 150- [16.91 ± 12.6%] textless 180-s [18.26 ± 12.87%]) (P textless 0.001). tHb was similar across time (P = 0.159) and between intensities (P = 0.454). HbDiff decreased (120- [73.56 ± 6.54%] textgreater 150- [71.66 ± 6.61%] textgreater 180-s [70.98 ± 6.93%]). StO2 decreased and then plateaued (120- textgreater 150- and 180-s) during the 70%BFR (51.87 ± 5.09% textgreater 51.20 ± 5.37% and 51.02 ± 5.21%) (P = 0.004), 80%BFR (52.2 ± 3.93% textgreater 51.34 ± 4.17% and 51.01 ± 4.09%) (P = 0.008), and 100%NOBFR (51.69 ± 4.6% textgreater 50.84 ± 4.87% and 50.62 ± 4.89%) (P textless 0.001) bouts, while there were no differences for 90%BFR (P textgreater 0.05). Conclusions Submaximal running with BFR induced similar responses as maximal running without, despite large differences (i.e., ≤30%) in running speed.