The Yangtze River Delta (YRD) Urban Agglomeration has been widely acknowledged as one of the regions with active economies while suffering high environmental pressure. This study established a Driving-Pressure-State-Impact-Response (DPSIR) eco-security evaluation model for measuring eco-security levels of 41 cities in the YRD. The weightings of all indices in the DPSIR model were determined by the entropy weight and the mean square error methods. The YRD Urban Agglomerations Eco-Security Index (YDESI) and eco-security levels of the 41 cities were calculated by principal component analysis and the comprehensive index method. The cities were then classified into four types by the eco-security level. The results suggested that the YRD region was at a critical value of the eco-security. Shanghai and Jiangsu Province had high eco-security levels; Zhejiang Province had a relatively high eco-security level; and Anhui Province had a worse eco-security level. The DPSIR model showed that Drivers and Response significantly influenced the eco-security of the YDR region. The main factors affecting the eco-security of the YRD Urban Agglomeration were agricultural development, ambient air quality, environmental investment and urban greening. Finally, this study proposed strategies for the YDR Urban Agglomeration by enhancing the regional population quality, new urbanization and infrastructure construction. The results provide more knowledge for the eco-security diagnosis and improvement in the YRD region and contribute to the development of an eco-security evaluation system for urban agglomeration.