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In advanced non-small cell lung cancer (NSCLC), patients with actionable genomic alterations may derive additional clinical benefit from targeted treatment compared to cytotoxic chemotherapy. Current guidelines recommend extensive testing with next generation sequencing (NGS) panels. We investigated the impact of using a targeted NGS panel (TruSight Tumor 15, Illumina) as reflex testing for NSCLC samples at a single institution. Molecular analysis examined 15 genes for hotspot mutation variants, including <i>AKT1</i>, <i>BRAF</i>, <i>EGFR</i>, <i>ERBB2</i>, <i>FOXL2</i>, <i>GNA11</i>, <i>GNAQ</i>, <i>KIT</i>, <i>KRAS</i>, <i>MET</i>, <i>NRAS</i>, <i>PDGFRA</i>, <i>PIK3CA</i>, <i>RET</i> and <i>TP53</i> genes. Between February 2017 and October 2020, 1460 samples from 1395 patients were analyzed. 1201 patients (86.1%) had at least one variant identified, most frequently <i>TP53</i> (47.5%), <i>KRAS</i> (32.2%) or <i>EGFR</i> (24.2%). Among these, 994 patients (71.3%) had clinically relevant variants eligible for treatment with approved therapies or clinical trial enrollment. The incremental cost of NGS beyond single gene testing (<i>EGFR</i>, <i>ALK</i>) was CAD $233 per case. Reflex upfront NGS identified at least one actionable variant in more than 70% of patients with NSCLC, with minimal increase in testing cost. Implementation of NGS panels remains essential as treatment paradigms continue to evolve.