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Introduction: EGFR tyrosine kinase inhibitor (TKI) is the standard adjuvant treatment for patients with stages IB to IIIA EGFR-mutated NSCLC. Nevertheless, adapting this approach to include a molecular residual disease (MRD)-guided de-escalation strategy warrants further investigation. Methods: From January 2019 to December 2022, 71 patients with stages I to III NSCLC and EGFR (exon 19 deletion or L858R) mutations were enrolled in this observational study. A total of 375 blood samples were analyzed using the MRD_Navigator assay. Among them, 27 patients suspended EGFR TKI treatment based on undetectable MRD and were thus included in the adaptive, de-escalation group. Results: Overall, the sensitivity of longitudinal MRD was 86.2%. Only four patients (11.8%) recurred with longitudinal undetectable MRD, indicating a negative predictive value of 88.2%. Of the patients who had detectable MRD after surgery, nine subsequently received EGFR TKI treatment, with only one (11.1%) achieving persistent circulating tumor DNA clearance post–EGFR TKI. Furthermore, 22 patients with stages IB to III disease who had previously suspended their TKI treatment based on undetectable MRD were included in the adaptive group, with an average duration of TKI 3.9 (range: 0–35.0) months. The 2-year disease-free survival rate of these 22 patients was 80.2%, and the median was not reached. Five patients (n = 5 of 22, 22.7%) had disease recurrence during the period of drug cessation but were stable under EGFR TKI treatment until the latest follow-up. Two patients remained in complete remission. Conclusions: Our initial findings underscore the potential of an adaptive, de-escalation approach to adjuvant EGFR TKIs based on circulating tumor DNA-MRD monitoring.