In the present work, semi-interpenetrating polymer networks (semi-IPNs) fabricated by the in situ synthesis of crosslinking networks between diamine cross-linkers and bromomethylated poly(phenylene oxide) (BPPO) are used toward sulfonated poly(ether ether ketone) (SPEEK) membrane applications for high concentration direct methanol fuel cells (DMFCs). Four kinds of diamine cross-linkers with different structures of hydrophobic flexible, hydrophilic flexible, hydrophobic rigid/ bulky, and hydrophilic rigid/bulky are applied to construct the semi-IPNs. The influences of cross-linkers on the key properties, such as phase separation, water uptake, proton conductivity, and methanol permeability, as well as cell performances, are systematically investigated. The results indicate that fabricating semi-IPNs is an attentive approach to improve the properties of SPEEK. The hydrophobic rigid/bulky fluorine cross-linker is the most effective to reduce methanol permeability, giving rise to the highest power output of the high concentration DMFC. In particular, by analyzing the correlation of cell performances, proton conductivity, and methanol permeability, we note that methanol permeability is more important than proton conductivity for high concentration DMFCs.