Photobiomodulation therapy (PBMt) combined or not with oral hypoglycemic medication has not been investigated in type 2 diabetes (T2DM) patients. All 10 T2DM patients were assessed randomly at 6 different occasions (3 with and 3 without regular oral hypoglycemic medication). Capillary glycemia was assessed after overnight fast (pre-prandial), 1 h postprandially (standardized meal, 338 kcal), and 30 min, 3 h, 6 h, 12 h post-PBMt (830 nm; 25 arrays of LEDs, 80 mW/array). Three doses (0 J—sham, 100 J, 240 J per site) were applied bilaterally on quadriceps femoris muscles, hamstrings, triceps surae, ventral upper arm and forearm; and randomly combined or not with oral hypoglicemic medication, totaling six different therapies applied for all 10 TDM2 patients (PBMt sham, PBMt 100 J, PBMt 240 J, PBMt sham + medication, PBMt 100 J + medication, PBMt 240 J + medication). Cardiac autonomic control was assessed by heart rate variability (HRV) indices. Without medication, there was reduction in glycemia after all PBMt doses, with 100 J as the best dose that persisted until 12 h and presented lower area under the curve (AUC). With medication, glycemia decreased similarly among doses. No differences between 100 J and sham + medication, but AUC was significantly lower after 100 J, suggesting better glycemic control. Low frequency component of HRV increased after sham + medication and 100 J, suggesting higher sympathetic activation. PBMt showed time– and dose–response effect to reduce glycemia in T2DM patients. Effects on HRV were consistent with glycemic control.