Background: Conventional tumor markers are positioned to serve as a useful adjunct in lung cancer management. However, most studies in this field have been specific to a particular disease stage or treatment regimen. Thus, the purpose of this research was to assess whether three minimally invasive, low-cost serum tumor markers (CEA, CA19-9, and CA-125) held associations with radiographic and clinical outcomes in non-small cell lung cancer (NSCLC) patients who received systemic therapy in a more comprehensive patient population. Methods: This was a single-center retrospective study of NSCLC patients treated between January 2016 and August 2020. Serum tumor markers were statistically analyzed for differences in patients who responded or progressed (RECIST 1.1 or iRECIST criteria), associations with demographic and clinical characteristics, and all-cause mortality in pre-defined populations. Disease response was assessed radiographically using RECIST 1.1 criteria. Results: From 533 NSCLC patients screened, 165 met inclusion criteria. Of these, 50.9% were male and 49.1% female. 69.7% had stage IV disease at baseline. The proportion of patients with an elevated CEA, CA-125, and CA19-9 at baseline were 58.8%, 50.9%, and 30.3%, respectively. A subset of 92 patients had paired tumor markers and radiographic scans, from which median (IQR) fold-change in tumor markers from nadir to progression was 2.13 (IQR 1.24 - 3.02; p < 0.001) for CEA (n = 47), 1.46 (IQR 1.13 - 2.18; p < 0.001) for CA19-9 (n = 46), and 1.53 (IQR 0.96 - 2.12; p < 0.001) for CA-125 (n = 47). Median (IQR) fold-change in tumor markers from baseline to radiographic response was 0.50 (IQR 0.27, 0.95; p < 0.001) for CEA (n = 39), 1.08 (IQR 0.74, 1.61; p = 0.99) for CA19-9 (n = 35), and 0.47 (IQR 0.18, 1.26; p = 0.008) for CA-125 (n = 35). Lastly, an elevated baseline CEA was not associated with a difference in overall survival (HR 1.05, 95% CI 0.63-1.74, p = 0.84) in patients with stage IV disease within the total population. Conclusions: Serum CEA, CA-125, and CA19-9 levels were significantly different than nadir in patients who progressed. CEA and CA-125 were significantly different than baseline in those who responded. These cost-effective tumor markers may serve as an important adjunct to clinical decision making. Analysis within a controlled clinical trial is warranted.