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In this paper, we interpret the 750 GeV diphoton excess in the Zee-Babuextension of the two-Higgs-doublet model by introducing a top partner($T$)/bottom partner ($B$). In the alignment limit, the 750 GeV resonance isidentified as the heavy CP-even Higgs boson ($H$), which can be sizablyproduced via the QCD process $pp \to T\bar{T}$ or $pp \to B\bar{B}$ followed bythe decay $T\to Ht$ or $B \to Hb$. The diphoton decay rate of $H$ is greatlyenhanced by the charged singlet scalars predicted in the Zee-Babu extension andthe total width of $H$ can be as large as 7 GeV. Under the current LHCconstraints, we scan the parameter space and find that such an extension canaccount for the observed diphoton excess.

Explaining 750 GeV diphoton excess from top/bottom partner cascade decay in two-Higgs-doublet model extension