Based on the perspective of the protection of Nanjing architectural culture in the Republic of China period, the work aims to explore the modern design inheritance path of Nanjing architectural genes in the Republic of China period and excavate new ideas for the design of cultural and creative products themed on Nanjing architecture in the Republic of China period under the assistance of artificial intelligence. Firstly, 25 representative buildings of Nanjing architecture in the Republic of China period were selected as the research objects, and the types of architectural genes of Nanjing architecture in the Republic of China period were analyzed according to the theory of architectural genes, and seven types of genes were mapped, including facade style, roof modeling, decorative pattern, color matching, building materials, spatial environment and emotional factors. Secondly, the analytic hierarchy method was used to calculate the weight of the gene map and select the design factors. Thirdly, the shape grammar was used to reconstruct the design factor, and the evolved design factor was input into the artificial intelligence software to generate 50 pattern samples. Finally, based on the SOR theoretical model, the experimental evaluation was carried out, and the samples that most conformed to the architectural style of Nanjing in the Republic of China period were selected for cultural and creative design. The gene map and judgment matrix evaluation model of Nanjing architecture in the Republic of China period were constructed and typical factors were selected and artificial intelligence software was used to generate patterns, forming a new model of intelligent design of cultural and creative products. The research on the extraction of architectural genes and intelligence-assisted design of Nanjing architecture in the Republic of China period shows that the genes of Nanjing architecture in the Republic of China period have the characteristics of inheritance, selection, replication and mutation, realizing the creative transformation and innovative development of architectural heritage, and showing the possibility of intelligence-assisted cultural and creative design, which enhances the cultural connotation of cultural and creative products.