Treatment resistance due to gene alterations remains a challenge for patients with EGFR-mutated advanced or metastatic non-small-cell lung cancer (a/mNSCLC). A systematic literature review (SLR) was conducted to describe resistance mutation profiles and their impact on clinical outcomes in adults with a/mNSCLC in the United States (US). A comprehensive search of MEDLINE and Embase (2018–August 2022) identified 2986 records. Among 45 included studies, osimertinib was the most commonly reported treatment (osimertinib alone: 15 studies; as one of the treatment options: 18 studies), followed by other tyrosine kinase inhibitors (TKIs; 5 studies) and non-TKIs (1 study). For first-line (1L) and second-line (2L) osimertinib, the most frequent EGFR-dependent resistance mechanisms were T790M loss (1L: 15.4%; 2L: 20.5–49%) and C797X mutation (1L: 2.9–12.5%; 2L: 1.4–22%). EGFR-independent mechanisms included MET amplification (1L: 0.6–66%; 2L: 7.2–19%), TP53 mutation (1L: 29.2–33.3%), and CCNE1 amplification (1L: 7.9%; 2L: 10.3%). For patients receiving osimertinib, EGFR T790M mutation loss, EGFR/MET/HER2 amplification, RET fusion, and PIK3CA mutation were associated with worse progression-free survival. Resistance mechanisms resulting from current NSCLC treatments in the US are complex, underscoring the need to address such heterogeneous resistance profiles and improve outcomes for patients with EGFR-mutated a/mNSCLC.