Abstract Background Eosinophilia is common in patients with atopic dermatitis (AD). Abrocitinib, an oral Janus kinase‐1 inhibitor and dupilumab, an anti–interleukin‐4 receptor‐α antibody, are approved for moderate‐to‐severe AD. Dupilumab has been associated with transient eosinophilia. Objectives To assess the effect of abrocitinib and dupilumab on eosinophils in patients from the phase 3 JADE COMPARE (NCT03720470) and JADE EXTEND (NCT03422822) trials. Methods In JADE COMPARE, patients received once‐daily oral abrocitinib (200/100 mg), placebo or subcutaneous dupilumab (300 mg, biweekly) with background topical therapy. In the ongoing long‐term JADE EXTEND study (Data cutoff: April 22, 2020), dupilumab‐treated patients from JADE COMPARE received once‐daily abrocitinib (200/100 mg) with background topical therapy. The proportion of patients with eosinophilia and hypereosinophilia, and association of eosinophilia with clinical efficacy was assessed. Adverse events (AEs) were also assessed. Results Of the 837 patients in JADE COMPARE, 58 (25.7%), 47 (19.7%) and 51 (21.1%) had eosinophilia at baseline in the abrocitinib 200 mg, abrocitinib 100 mg and dupilumab groups, respectively. At Week 16, eosinophilia decreased with abrocitinib 200 mg (9.3%) and abrocitinib 100 mg (19.0%) but not dupilumab (21.5%); no cases of hypereosinophilia were observed with abrocitinib 200 mg compared with abrocitinib 100 mg (1.9%) and dupilumab (2.3%). Decreases in median eosinophil counts were greater with abrocitinib 200 mg (difference, −100/mm 3 ) and abrocitinib 100 mg (−70/mm 3 ) than dupilumab (+25/mm 3 ) or placebo (+30/mm 3 ) at Week 16. Similar trends were observed in patients with comorbid asthma and allergic rhinitis. Eosinophilia decreased from baseline to Week 12 in dupilumab‐treated patients who switched to abrocitinib in JADE EXTEND. Decreased eosinophil counts with abrocitinib correlated positively with improvements in AD severity, itch and sleep loss. No eosinophilia‐associated AEs occurred. Conclusions Abrocitinib decreased eosinophilia in patients with moderate‐to‐severe AD who had baseline eosinophilia. Resolution of eosinophilia was associated with abrocitinib clinical efficacy.