Exosomes are messengers for intercellular communication and signal transduction. Circular RNA (circRNA) abnormal expression and regulation are involved in the occurrence and development of a variety of tumors. In the present study, exosomes in the serum of five patients with non-small cell lung cancer (NSCLC) were isolated before and after EGFR-TKIs resistance, and the circRNA expression profile was screened using a circRNA microarray. The effects of the exosome circRNA_102481 on cell proliferation and apoptosis were analyzed. The interaction between miR-30a-5p and circRNA_102481 or ROR1 was predicted by starBase software, and was confirmed by RNA pull-down and dual-luciferase reporter assays. The results showed that exosomes containing circRNA_102481 were significantly up-regulated in NSCLC with EGFR-TKIs resistance (p<0.05), and that circRNA_102481 was mainly secreted by EGFR-TKIs resistance cell via exosomes (p<0.05). Both circRNA_102481 silencing and si-circRNA_102481 transported by exosomes could inhibit EGFR-TKIs resistance cell proliferation and promote cell apoptosis and circRNA_102481 overexpression could promote EGFR-TKIs sensitive cell proliferation and inhibit cell apoptosis in vitro (p<0.05). CircRNA_102481 served as a miR-30a-5p sponge to regulate ROR1 expression (p<0.05). Furthermore, the expression of circRNA_102481 in exosomes was associated with TNM stage, tumor differentiation status, brain metastasis, and PFS and OS duration. Therefore, it was concluded that tumor-derived exosomal circRNA_ 102481 could contribute to EGFR-TKIs resistance via the microRNA-30a-5p/ROR1 axis in NSCLC. Exosomal circRNA_102481 may serve as a novel diagnostic biomarker and a therapeutic target for EGFR-TKIs resistance in NSCLC.