Atopic dermatitis (AD) is a common inflammatory skin disease. Cognitive dysfunction was recently demonstrated to be increased in adults and children with AD. However, little is known about the longitudinal course of cognitive impairment in AD and its relationship with pruritus. To investigate the longitudinal course and predictors of cognitive impairment in AD a prospective dermatology practice-based study was performed using questionnaires and evaluation by a dermatologist (n = 210). Patients with ≥ 2 visits were included (mean follow-up time: 318 days). Cognitive function was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function 8-item Short-Form. At baseline, 20.85% of patients had PROMIS T scores ≤ 45, indicating cognitive impairment (CI). Among patients with CI at baseline, 34.09% had persistent CI, 47.72% had a fluctuating course, and 18.18% had sustained improvement of cognitive function. In repeated-measures regression models, cognitive function scores declined overtime in patients with worse AD severity [SCORing Atopic Dermatitis (SCORAD): p = 0.01, Atopic Dermatitis Severity Index: p = 0.001], increased itch (p = 0.01), skin pain (p = 0.001), and sleep disturbance (p = 0.001). In multivariable logistic regression models, persistent CI was associated with female gender and depressive symptoms [moderate-to-severe Patient Health Questionnaire-9 score (PHQ9)]. Latent class analysis identified two classes of cognitive dysfunction: normal cognition (77.23%), moderate dysfunction (16.21%) and severe impairment (6.55%). Black/African-American race (p = 0.02), moderate-to-severe SCORAD (p = 0.03), dermatology life quality index (p < 0.0001), PHQ9 (p < 0.0001), itch (p = 0.02) and skin pain (p < 0.0001) were more likely to experience moderate dysfunction or severe cognitive impairment. AD is associated with a heterogeneous longitudinal course of cognitive function in adults, with some patients experiencing persistent CI over time.