Background <p>Esophageal squamous cell carcinoma (ESCC) is a prevalent gastrointestinal malignancy characterized by a high incidence and mortality rate. ESCC frequently develops drug resistance during chemotherapy, resulting in diminished clinical efficacy. Previous studies have identified SNHG16, a long non-coding RNA, as a crucial oncogene, but its underlying mechanisms in the biological functions and chemoresistance regulation in ESCC remain unclear.</p> Methods <p>RT-qPCR and western blotting were utilized to detect SNHG16, miR-497-5p, and HK2 expression in DDP-resistant/sensitive ESCC tissues and cells. In vitro functional experiments were performed by transfecting DDP-resistant ESCC cells lines with sh-SNHG16, including CCK8, flow cytometry, EdU assay, and transwell assay. Mechanistically, the mechanistic aspects and target binding relationship were established through the luciferase reporter assay. In vivo xenograft model was established to examine the impact of SNHG16.</p> Results <p>SNHG16 was significantly overexpressed in both DDP-resistant ESCC tissues and cells. Functional in vitro studies demonstrated that silencing SNHG16 significantly inhibited the proliferation, migration and invasion of ESCC cells, induced cell apoptosis, and sensitized DDP-resistant cells to DDP. Moreover, SNHG16 exerted malignant biological behavior in ESCC cells and conferred cisplatin resistance by acting as a sponge for miR-497-5p and regulating HK2.</p> Conclusions <p>Our findings uncovered that SNHG16 promoted ESCC malignant progression and DDP resistance through the miR-497-5p/HK2 axis, laying the groundwork for deciphering the molecular mechanisms underlying chemotherapy resistance in ESCC and developing new treatment strategies.</p>