Background: Neoadjuvant immunotherapy (ICI) plus chemotherapy (CT) provides a significant benefit compared to CT alone in resectable non-small cell lung cancer (NSCLC). However, further research is needed to identify the populations benefitting from this combined strategy. Methods: Patients (pts) diagnosed with stage II-III resectable NSCLC who opted for neoadjuvant ICI plus CT were enrolled. Plasma samples were collected before treatment initiation (T1) and before surgery (T2). A next-generation sequencing (NGS) platform spanning 769 cancer-related genes was utilized to detect circulating tumor DNA (ctDNA). The ctDNA concentration was presented as haploid genome equivalents (hGE) per mL of plasma. Additionally, low-pass whole-methylome sequencing was employed to explore three features of cell-free DNA, including methylated fragment ratio (MFR), fragment size index (FSI), and chromosomal aneuploidy of featured fragments (CAFF). Clinical and pathological data was obtained from medical records. Results: Out of 24 pts enrolled, 18 pts were evaluable on both platforms. The major pathological response (MPR) rate was 70.8% (17/24), and the pathological complete response (pCR) rate was 37.5% (9/24). Squamous cell carcinoma (SCC) showed a higher MPR rate than adenocarcinoma (P = 0.014). Pts with clinical T stage 2 showed a trend toward a higher MPR rate than those with T stage 3/4 (P = 0.069). No single molecular biomarker was found to be independently associated with MPR or pCR at T1. A linear discriminant model was constructed based on clinical T stage, MFR, and hGE at T1, which predicted both MPR and pCR with an accuracy of 83.3% (n = 18). In pts with SCC (n = 15), the accuracy of this model in predicting MPR and pCR was 80.0% and 86.7%, respectively. Moreover, the CAFF score at T2 was significantly higher in non-MPR pts than in MPR pts (P = 0.003). The dynamic change of CAFF score [calculation: (T2-T1) / T1] was also significantly related to MPR (P = 0.006). Conclusions: Baseline cfDNA features and clinical parameters effectively predicted pathological response of neoadjuvant ICI plus CT in resectable NSCLC, which could potentially serve as a tool for identifying patients that would benefit most from the combined approach.