Objective Globally, cervical cancer is the second most common cancer among women, and determining potential targets involved in tumor progression is necessary. This study investigated the clinic-pathological significance of twist homolog 2 (TWIST2), a basic helix–loop–helix transcription factor, and correlated TWIST2 and E-cadherin expression in cervical cancer. Methods A series of 142 samples, including 14 cases of normal cervical tissues, 58 cases of cervical intraepithelial neoplasia (CIN) and 70 cases of squamous cell carcinoma (SCC), were examined TWIST2 and E-cadherin immunohistochemical staining and statistical analysis. Results Increased cytoplasmic and nuclear expression levels of TWIST2 were associated with the malignant transformation of cervical epithelium and the histological progression of cervical cancer. A logistic test showed that TWIST2 was a relatively independent predictor of lymph node metastasis of SCC. Further, increased levels of TWIST2 were also associated with aberrant expression of E-cadherin, an important EMT indicator. Conclusions The present data suggest that TWIST2 overexpression was significantly linked to cervical cancer progression, which makes it a promising marker for determining the metastatic potential of cervical cancer, and up-regulation of TWIST2, in combination with aberrant E-cadherin expression in primary cervical cancer tissues, may predict the malignant transformation and distal metastasis of carcinomas.