Purpose: An overall trend is observed towards de-escalation of axillary surgery in patients with breast cancer. The objective of this study was to evaluate this trend in patients treated with neoadjuvant systemic therapy (NST). Methods: Patients with cT1-4N0-3 breast cancer treated with NST (2006–2016) were selected from the Netherlands Cancer Registry. Patients were classified by clinical node status (cN) and type of axillary surgery. Uni- and multivariable logistic regression analyses were performed to determine the clinicopathological factors associated with performing ALND in cN+ patients. Results: A total of 12,461 patients treated with NST were identified [5830 cN0 patients (46.8%), 6631 cN+ patients (53.2%)]. In cN0 patients, an overall increase in sentinel lymph node biopsy (SLNB) only (not followed by ALND) was seen from 11% in 2006 to 94% in 2016 (p < 0.001). SLNB performed post-NST increased from 33 to 62% (p < 0.001). In cN+ patients, an overall decrease in ALND was seen from 99% in 2006 to 53% in 2016 (p < 0.001). Age (OR 1.01, CI 1.00–1.02), year of diagnosis (OR 0.47, CI 0.44–0.50), HER2-positive disease (OR 0.62, CI 0.52–0.75), clinical tumor stage (T2 vs. T1 OR 1.32, CI 1.06–1.65, T3 vs. T1 OR 2.04, CI 1.58–2.63, T4 vs. T1 OR 6.37, CI 4.26–9.50), and clinical nodal stage (N3 vs. N1 OR 1.65, CI 1.28–2.12) were correlated with performing ALND in cN+ patients. Conclusions: ALND decreased substantially over the past decade in patients treated with NST. Assessment of long-term prognosis of patients in whom ALND is omitted after NST is urgently needed.