Background: Cachexia and weight loss have been linked to poor outcomes in patients with cancer. This study’s aim was to conduct a meta-analysis to estimate the risk of mortality associated with cachexia in patients with non-small cell lung cancer (NSCLC) in studies identified through a systematic literature review (SLR). Methods: A feasibility assessment was undertaken to determine the suitability of conducting a meta-analysis evaluating the impact of cachexia, defined per International Consensus criteria (ICC) or previous weight loss (WL) ≥5% (without specifying a 6-month duration), on overall survival (OS) in patients with NSCLC. The meta-analysis was conducted using a random-effects model, considering variability across studies, and using the identified studies as base case. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. Standard measures of statistical heterogeneity were calculated for each meta-analysis. Results: Of the 40 NSCLC publications identified in the SLR, 20 (50%) used the ICC definition or reported WL ≥5%. Sixteen studies (80%, n = 6,225 patients, published in 2016 to 2021) met the criteria for inclusion in the meta-analysis: 11 (69%) studies per ICC and 5 (31%) studies per WL ≥5%. Combined criteria (ICC or WL ≥5%) were associated with 82% higher mortality risk versus no cachexia or WL < 5% (pooled hazard ratio [95% CI]: 1.82 [1.47, 2.25]). A subgroup analysis of studies using the ICC definition (hazard ratio [95% CI]: 2.26 [1.80, 2.83]) or WL ≥5% (hazard ratio [95% CI]: 1.28 [1.12, 1.46]) showed consistent findings. Although high statistical heterogeneity (I-square = 88%) was observed across studies, this variability could be disregarded because effect estimates (hazard ratios) from included studies were directionally aligned with considerable overlap in CIs of individual studies. A meta-influence analysis did not identify any potential outliers. Results of the sensitivity and subgroup analyses were consistent with the base case analysis. Cumulative meta-analyses by publication year or data collection midpoint identified no time-varying effect, indicating results were robust to the differing timeframes of publication or data collection. No substantial publication bias, measured via funnel plot analysis, was identified in the meta-analysis. Conclusions: Based on thorough methodologic, clinical, and statistical heterogeneity assessments, the meta-analysis results are robust. ICC-defined cachexia or WL ≥5% were associated with inferior OS in patients with NSCLC. Identifying cachexia or WL ≥5% has important implications for prognosis and treatment of NSCLC.