Background: Several single-arm prospective studies have demonstrated the safety and effectiveness of upper airway stimulation (UAS) for obstructive sleep apnea. There is limited evidence from randomized, controlled trials of the therapy benefit in terms of OSA burden and its symptoms. Methods: We conducted a multicenter, double-blinded, randomized, sham-controlled, crossover trial to examine the effect of therapeutic stimulation (Stim) versus sham stimulation (Sham) on the apnea-hypopnea index (AHI) and the Epworth Sleepiness Scale (ESS). We also examined the Functional Outcomes of Sleep Questionnaire (FOSQ) on sleep architecture. We analyzed crossover outcome measures after two weeks using repeated measures models controlling for treatment order. Results: The study randomized 89 participants 1:1 to Stim (45) versus Sham (44). After one week, the AHI response rate was 76.7% with Stim and 29.5% with Sham, a difference of 47.2% (95% CI: 24.4 to 64.9, p < 0.001) between the two groups. Similarly, ESS was 7.5 ± 4.9 with Stim and 12.0 ± 4.3 with Sham, with a significant difference of 4.6 (95% CI: 3.1 to 6.1) between the two groups. The crossover phase showed no carryover effect. Among 86 participants who completed both phases, the treatment difference between Stim vs. Sham for AHI was −15.5 (95% CI −18.3 to −12.8), for ESS it was −3.3 (95% CI −4.4 to −2.2), and for FOSQ it was 2.1 (95% CI 1.4 to 2.8). UAS effectively treated both REM and NREM sleep disordered breathing. Conclusions: In comparison with sham stimulation, therapeutic UAS reduced OSA severity, sleepiness symptoms, and improved quality of life among participants with moderate-to-severe OSA.