Irregular structural layout due to the change of plan and elevation shape is usually considered a negative factor to the material usage of the structure. Therefore, the current green building evaluation manual in Taiwan also discourages the design of irregular building shapes. This research was aimed to investigate the actual effect of varying structural layout on the material usage and carbon emission. Computer structural models were established for hypothetical low-rise RC buildings. Experimental models were developed with four types of variation, including: discontinuous beams, oblique beams, deviate beams, and cantilever. Structural member sections of the models were designed in accordance with the present structural design procedure in Taiwan. Concrete and steel usage and the corresponding CO2 emission were then calculated. The results showed that when there were incomplete frames due to discontinuous beams in the structural layout, the material usage and CO2 emission significantly increased. Oblique beams and deviate beams did not obviously affect the structural behavior and the material usage. A reduction of CO2 emission per unit floor area was found in the models with cantilevers because the increase in material usage was not proportional to the increase in floor area. These results suggested that the continuity of structural members is a more essential factor than the geometric regularity of structural layout for the design of economic structures. The smart use of cantilevers might be an efficient strategy to reduce the carbon emission and achieve the design variety simultaneously.