The increased metastatic ability of small-cell lung cancer (SCLC) necessitates the identification of new prognostic biomarkers for clinical evaluation during the disease course. Our previous research highlighted the clinical relevance of transcription factor JunB (JUNB), C-X-C chemokine receptor type 4 (CXCR4), and programmed cell death 1 ligand 1 (PD-L1) in breast and non-small cell lung cancer (NSCLC) patients. In the current study, we examined these biomarkers in circulating tumor cells (CTCs) and plasma-derived exosomes from 100 treatment-naïve SCLC patients. CTCs were analyzed using the VyCAP system, whereas exosomes were characterized molecularly and transcriptomically. JUNB, CXCR4, and PD-L1 were highly prevalent in CTCs. Patients exhibited significantly increased protein exosomal expression of JUNB and CXCR4 compared to healthy individuals. Overexpression of JUNB and CXCR4 in exosomes can distinguish patients from normal donors, offering an interesting tool for early diagnosis. The presence of JUNB and/or CXCR4 in CTCs correlated with significantly poorer overall survival. CXCR4 exosomal overexpression was associated with CTC presence and their phenotypes. Conclusively, a comprehensive analysis of CTCs and exosomes provides useful prognostic and potential diagnostic tools for SCLC patients.