Background . The efficacy and safety of esketamine nasal spray (ESK) were established in registration trials in patients with treatment‐resistant depression (TRD). This French real‐world study aimed to describe the treatment patterns, effectiveness, and safety of ESK in TRD patients over a 12‐month follow‐up. Materials and Methods . This study used secondary data from patient files of hospital‐based psychiatrists and started during the first French patient early access to ESK. The response and remission rates with ESK were analyzed using the total score of the Montgomery–Åsberg Depression Rating Scale (MADRS). The time to first treatment response and work resumption were described (Kaplan–Meier method). Adverse events (AEs) were analyzed. Results . Prior to ESK initiation, the 157 analyzed patients (age ≤ 65 years, 82.8%; female, 66.2%) had depression for 10.5 years (median, IQR, 4.2–21.2) and received a median of 6 (3–8) previous treatment lines. At ESK initiation, the mean ± SD total MADRS score was 32.1 ± 7.7. At that time, ESK was combined with antidepressants (93.6% of patients; SNRI, 65.0%; SSRI, 57.3%) and/or other potentiation strategy (63.1%; atypical antipsychotics, 36.3%; lithium, 25.6%; antiepileptics, 21.7%). During the 12‐month follow‐up, 125 patients (79.6%) discontinued ESK. The median duration of ESK treatment was 19.4 weeks (IQR, 4.4–40.1). At 1 month after ESK initiation, 40.2% of still treated patients met criteria for clinical response and 19.7% for remission (median time to response, 5.7 weeks; 95% CI (4.1–8.4)). 82.6% of active patients were on sick leave at ESK initiation; the work resumption rate was 24% (13%–40%) 12 weeks later. AEs were reported in 68.6% of patients, serious AEs in 17.2%, and AEs leading to ESK discontinuation in 14.6%. Conclusion . These real‐world effectiveness and safety data were consistent with findings from previous clinical trials, describing the real‐life clinical experience of patients receiving ESK and confirming that ESK has its place in therapy for the treatment of TRD.