Obstructive sleep apnea (OSA) is a chronic disorder characterized by recurrent episodes of upper airway collapse during sleep, which can lead to serious health issues like cardiovascular disease and neurocognitive impairments. While positive airway pressure serves as the standard treatment, intolerance in some individuals necessitates exploration of alternative therapies. Hypoglossal nerve stimulation (HGNS) promises to mitigate OSA morbidity by stimulating the tongue muscles to maintain airway patency. However, its effectiveness varies, prompting research for optimization. This review summarizes the effects of HGNS on upper airway obstruction from human and animal studies. It examines physiological responses including critical closing pressure, maximal airflow, nasal and upper airway resistance, compliance, stiffness, and geometry. Interactions among these parameters and discrepant findings in animal and human studies are explored. Additionally, the review summarizes the impact of HGNS on established OSA metrics, such as the apnea-hypopnea index, oxygen desaturation index, and sleep arousals. Various therapeutic modalities, including selective unilateral or bilateral HGNS, targeted unilateral HGNS, and whole unilateral or bilateral HGNS, are discussed. This review consolidates our understanding of HGNS mechanisms, fostering exploration of under-investigated outcomes and approaches to drive advancements in HGNS therapy.