Background: Significant toxicity is common in the treatment of advanced non-small cell lung cancer (NSCLC) and can be associated with adverse events, such as unplanned hospitalization, and worse clinical outcomes. Baseline low skeletal muscle (SM) area is a marker of sarcopenia and has been associated with worse survival in other malignancies, but the association of SM area and toxicity in NSCLC is less studied. Methods: Patients with locally advanced or oligo-metastatic NSCLC treated with combined chemotherapy and radiotherapy with or without surgery from 2002-2013 at a single institution were reviewed. A deep-learning pipeline utilized existing pre-treatment computed tomography scans to calculate SM area at the 3rd lumbar vertebral level. Gold standard SM index (SMI) was calculated, adjusting for height, sex, and dichotomized per previously validated cutoff values. Grade 3 or higher hematologic (G3+ heme) toxicity, was assessed per NCI CTCAE v5.0, within 21-days of first chemotherapy cycle. Hospital use was defined as unplanned ED visit or inpatient hospitalization during chemotherapy. Multivariate analysis (MVA) of toxicity endpoints with SMI and baseline characteristics were analyzed by logistic regression analysis, and with overall survival (OS) using Cox regression analysis. Results: A total of 369 patients met inclusion criteria with median follow-up of 23.0mo (range 1-193mo), median age of 64y (range 29-88y), and were mostly male (51%). Most were clinical stage (AJCC 7th edition) IIIA (44%), IIIB (31%), or IV (10%), while 10% had upfront surgery and adjuvant chemotherapy. Most common regimen was cisplatin-based (48%). Median OS was 25.5mo and PFS was 14.0mo. Patients with low SMI were more likely to be younger (median age 70y vs 62y), ECOG performance status (PS) > 0 (74% vs 59%), lower BMI (median BMI 23.3 vs 27.7), and not receive cisplatin-based regimen (35% vs 53%). There was no difference in histology, stage, surgery, or every 3-week (q3w) chemotherapy dosing. On MVA, low SMI was associated with increased risk of G3+ heme toxicity (OR 1.74, p = 0.04) and increased hospital use (OR 1.79, p = 0.04). G3+ heme toxicity was also associated with surgery and q3w dosing, but not age, PS, BMI, or regimen. Hospital use was also associated with BMI, surgery, and cisplatin-based regimen, but not age, PS, or q3w dosing. G3+ heme toxicity (HR 1.48, p < 0.01), older age (HR 1.02, p = 0.02), and stage 4 (HR 3.32, p < 0.01) were associated with worse survival on MVA, but not low SMI (HR 1.25, p = 0.11), PS, BMI, surgery, or regimen. Conclusions: Low SMI predicted higher risk of G3+ toxicity during first cycle of chemotherapy. High-risk patients with low SMI experienced significant adverse events and should be considered for more aggressive symptom management or alternative treatment strategies.