The standard first-line treatment for metastatic non-small cell lung cancer (NSCLC) without oncogenic alterations and programmed death-ligand 1 (PD-L1) expression < 1% is a combination of chemotherapy (CT) and immunotherapy (IO). However, real-world overall survival (OS) appears more modest than in clinical trials, averaging 10–13 months. This retrospective study aimed to assess treatment patterns and real-world outcomes at the Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). Patients diagnosed between January 2019 and December 2023 with advanced PD-L1 <1% NSCLC and treated with palliative intent at IUCPQ were included and categorized by first-line treatment. Progression-free survival (PFS) and OS of the CT + IO and CT groups were compared using Kaplan–Meier curves and Cox regression analyses. Data regarding regimen selection, adverse events and subsequent treatment lines were collected. Among 217 eligible patients, 82 (37.8%) received CT + IO, 32 (14.7%) CT alone, 16 (7.4%) targeted therapy, and 87 (40.1%) supportive care. Median PFS was 5.3 vs. 4.7 months (p = 0.5) and OS 14.4 vs. 13.5 months (p = 0.2) for CT + IO and CT alone, respectively. In the CT + IO group, treatment discontinuation was mainly due to disease progression (59.4%) or adverse events (36.2%). Immune-related adverse events occurred in 29.3%, most frequently pneumonitis (8.5%). Therefore, in this cohort, no statistically significant survival difference was observed between CT + IO and CT alone. However, these findings should be interpreted cautiously given the non-randomized design, baseline imbalances between groups, and the limited sample size of the CT alone cohort. Tolerability of CT + IO was consistent with that observed in clinical trials.