Contaminants, such as pathogens or non-living substances, can spread through the interaction of their carriers (e.g., air and surfaces), which constitute a network. The structure of such networks plays an important role in the contaminant spread. We measured the contaminant spreading efficiency in different networks using a newly defined parameter. We analyzed basic networks to identify the effect of the network structure on the contaminant spread. The spreading efficiency was highly related to some network parameters, such as the source node’s average path length and degree, and considerably varied with the transfer rate per inter-node interaction. We compared the contaminant spreading efficiencies in some complex networks, namely scale-free, random, regular-lattice, and bipartite networks, with centralized, linear, and fractal networks. The contaminant spreading was particularly efficient in the fractal network when the transfer rate was ~0.5. Two categories of experiments were performed to validate the effect of the network structure on contaminant spreading in practical cases: (I) gas diffusion in multi-compartment cabins (II) bacteria transfer in multi-finger networks. The gas diffusion could be well estimated based on the diffusion between two compartments, and it was considerably affected by the network structure. Meanwhile, the bacteria spread was generally less efficient than expected.