Monomers with low symmetries can form different topological structures in the preparation of organic two-dimensional (2D) materials. However, it remains challenging to modulate the topologies in practical synthesis. Leveraging theoretical insights into the formation energy of potential structural configurations, we report the topology modulation of a graphdiyne (GDY) derivative constructed from two-fold symmetric tetrakis(4-ethynylphenyl)ethene precursor by changing solvent combinations in a liquid–liquid interfacial system. An aqueous–organic (water–dichloromethane) interface afforded GDY with a kagome topology while a rhombic topology was formed at an organic–organic (hexane–acetonitrile) interface. A comprehensive evaluation of their structures and optoelectronic properties was conducted through various characterization techniques and theoretical computations. Our study provided new insights to modulate the topology of not only GDY but also other framework structures and obtain topologically pure materials in situations where different topologies are possible during practical synthesis.