The simultaneous exhibition of Salus Populi Romani (Collection of the Church of Sant’Andrea, Rome, Italy) at the National Museum of China and the Chinese Madonna Scroll attributed to Tang Yin (Collection of the Field Museum of Natural History, USA) has long been a subject of academic discussion due to the striking visual similarities between the two works. This paper employs literature review and image analysis methods to systematically review and compare relevant historical documents and visual materials. The study finds that while the Chinese Madonna Scroll attributed to Tang Yin was a forgery, it was created under the influence of multiple factors in the late Ming period such as the economic development of the Suzhou region, the admiration for famous artists, and the exchange of Chinese and Western art. The scroll is a product of the unique “Suzhou Pian” from the Jiangnan art scene in the late Ming period. This cross-cultural creation cannot simply be understood as imitation or misinterpretation, nor can it be explained through the binary framework of “authenticity vs. forgery” or “influence vs. being influenced.” Instead, it reveals the multi-layered intermediary structures and re-creative logic formed through the interaction of different cultural systems. Additionally, by diminishing the religious attributes of the image, the Chinese Madonna Scroll increased its social acceptability, transforming it from a religious object into a secular art piece for aesthetic enjoyment and display. Therefore, this work serves as an important example of cross-cultural exchange and its transformation at the popular level during the Ming periods.