It is an important task to discover the linguistic differences between South and North during the Southern and Northern Dynasties period. Prior discussions have always concentrated on phonological aspects, while lexical studies are nearly entirely absent. In this paper, we propose a systematic methodology to unearth lexical differences. By investigating diachronic substitutions of disyllabic structures relating to words for “eye”, we observe that the northerners tended to use the ancient word mu 目 while the southerners adopted the new word yan 眼 in formal writing. This conclusion partly confirms Yan Zhitui’s point: “southerners often use vernacular words while northerners use archaisms.” In the future, more studies of this kind will reveal the overall lexical differences between South and North, and will help us to understand the “Yan Zhitui Puzzle”.