Objective To explore the effects of circ_100284 in affecting the invasion of esophageal squamous cell carcinoma (ESCC) cells and their sensitivity to 5-fluorouracil (5-FU) chemotherapy via regulating miR-217/mitogen-activated protein kinase 1 (MAPK1) acting as a competing endogenous RNA (ceRNA). Methods The bioinformatics approach was used to analyze the differentially expressed circRNAs in ESCC. qRT-PCR was used to detect the expression of circ_100284 in ESCC tissues and cells. The 5-FU-resistant KYSE450 cell line (KYSE45-R) was established by increasing concentrations of 5-FU. The IC₅₀ of 5-FU in KYSE450 and KYSE450-R cells was determined through MTT assay. qRT-PCR was used to detect the expression of circ_100284, miR-217, and MAPK1 mRNA in KYSE450 and KYSE450-R cells, while Western blotting detecting the protein expression of MAPK1. In the experiments with KYSE450-R cells, we set up the following groups: (1) blank group (without treatment), si-NC group (transfected with si-NC), si-circ_100284 group (transfected with si-circ_100284), pc-Control group (transfected with pc-Control), pc-circ_100284 group (transfected with pc-circ_100284), pc-circ_100284+mimic NC group (transfected with pc-circ_100284 and mimic NC), and pc-circ_100284+miR-217 mimic group (transfected with pc-circ_100284 and miR-217 mimic). These groups were subjected to MTT assay to detect cell viability, Transwell assay to detect cell invasion, and flow cytometry to detect cell apoptosis. (2) Blank group (without treatment), si-NC group (transfected with si-MAPK1 negative control), si-MAPK1 group (transfected with si-MAPK1), si-MAPK1+inhibitor NC group (transfected with si-MAPK1 and inhibitor NC), and si-MAPK1+miR-217 inhibitor group (transfected with si-MAPK1 and miR-217 inhibitor). We detected the mRNA and protein expression of MAPK1 using qRT-PCR and Western blotting. We evaluated cell viability using MTT assay, invasion with Transwell assay, and apoptosis by flow cytometry. circ_100284-WT or circ_100284-MUT reporter plasmids, as well as MAPK1-WT or MAPK1-MUT reporter plasmids, were co-transfected with miR-NC or miR-217 mimic into KYSE450-R cells for 48 h, and dual luciferase reporter assay was used to measure luciferase activity. Results The bioinformatics analysis revealed significant upregulation of circ_100284 in ESCC. Compared with adjacent normal tissues, the expression of circ_100284 in ESCC tissues is enhanced (P<0.05); compared with the HECC cells, the TE-11, ECA109 and KYSE450 ESCC cell lines showed enhanced expression of circ_100284 (P<0.05). Compared with the KYSE450 cells, KYSE450-R cells demonstrated increased IC₅₀ with enhanced expression of circ_100284 and MAPK1 but suppressed expression of miR-217 (P<0.05). Compared with the si-NC group, the si-circ_100284 group demonstrated inhibited invasion and proliferation of cells with increased apoptosis (P<0.05). Compared with pc-Control group, the invasion and proliferation of cells in the pc-circ_100284 group are increased, and cell apoptosis is decreased (P<0.05). Over-expression of miR-217 reversed the malignant biological behavior of ESCC cells induced by pc-circ_100284 (P<0.05). Compared with si-NC group, in the si-MAPK1 group, we observed decreased cell invasion and proliferation, and increased apoptosis (P<0.05), but miR-217 inhibitor reversed the effect of si-MAPK1 on the biological behavior of ESCC cells (P<0.05). The targeting relationship of circ_100284 and miR-217, miR-217 and MAPK1 is confirmed. Conclusion circ_100284 promotes ESCC cell invasion by regulating miR-217/MAPK1, inhibits the chemosensitivity of ESCC cells to 5-FU, and acts as a tumor-promoting factor in ESCC.