ABSTRACTData from the REST‐ON trial were not available before the 2021 American Academy of Sleep Medicine (AASM) clinical practice guideline update, which included a literature review through August 2020. This post hoc analysis from REST‐ON assessed participants who achieved clinically significant improvements on individual AASM clinical significance thresholds (CSTs). Composites of the coprimary endpoints and a secondary endpoint were also analysed. Participants with narcolepsy aged ≥ 16 years were randomised 1:1 to once‐nightly sodium oxybate (ON‐SXB) or placebo for 13 weeks. Coprimary endpoints were mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression of Improvement (CGI‐I) rating, and number of cataplexy episodes; secondary endpoints included the Epworth Sleepiness Scale (ESS) score. Outcomes with ON‐SXB treatment compared with baseline were assessed according to the CSTs, and for those who met CSTs, the proportions of participants who experienced clinically significant improvements on a composite of ≥ 2, ≥ 3, or 4 endpoints were calculated. For improvements from baseline with ON‐SXB at Week 13 (9‐g dose), mean sleep latency on the MWT increased 10.8 min (CST, ≥ 2‐min increase), 92.8% rated improvement on the CGI‐I (CST, ≥ 33% of participants reporting improvement), reduction in number of cataplexy episodes was 60.8% reduction (CST, ≥ 25% reduction), and reduction in ESS score was −6.5 (CST, ≥ 2‐point decrease). At Weeks 3, 8 and 13, significantly more participants treated with ON‐SXB versus placebo experienced clinical improvements on ≥ 2, ≥ 3, or 4 endpoints (p ≤ 0.05). These data demonstrate the robust efficacy of ON‐SXB across multiple clinically important narcolepsy symptoms per established CSTs, further supporting the use of ON‐SXB in clinical practice.Trial Registration: This manuscript presents the results of a post hoc analysis from the REST‐ON clinical trial (NCT02720744).