The rapid growth of resource-limited systems, such as the Internet of Things (IoT), embedded systems and wireless sensor networks has created a pressing need for efficient and secure cryptographic schemes. Another growing trend is lightweight block ciphers, which provide an alternative to such conventional encryption algorithms as AES, and are less resource-intensive. The paper has proposed to address this issue with a unified structural analysis and cryptanalytic evaluation framework which is an amalgam of algebraic and differential approaches. This paper seeks to provide a rigorous, comprehensive and quantitative evaluation of lightweight block ciphers’ security. The proposed method describes the operations of a cipher as many-to-many multivariate polynomial systems in finite fields, and at the same time it considers the differential propagation by using difference distribution tables (DDTs). A combined security measure Lis proposed to quantify the balance between the algebraic degree and differential probability, to offer a multi-dimensional view of the cipher security. The experimental results are based on the analysis of typical lightweight ciphers PRESENT, SIMON and GIFT. From the results, it is clear that the proposed framework can perform better security analysis, with a higher degree of algebra (up to 25), lower differential probability (as low as 0.015) and attack efficiency (around 42.3%) than the previous techniques. Moreover, the comparative study does confirm that the integrated approach can provide a better understanding of cipher vulnerabilities and strengths.