Abstract: In this paper, we interpret the 750 GeV diphoton excess in the Zee-Babu extension of the two-Higgs-doublet model by introducing a top partner (T)/bottom partner (B). In the alignment limit, the 750 GeV resonance is identified as the heavy CP-even Higgs boson (H), which can be sizably produced via the QCD process pp -> T (T) over bar or pp -> B (B) over bar followed by the decay T -> Ht or B -> Hb. The diphoton decay rate of His greatly enhanced by the charged singlet scalars predicted in the Zee-Babu extension and the total width of H can be as large as 7 GeV. Under the current LHC constraints, we scan the parameter space and find that such an extension can account for the observed diphoton excess.