Phospholipase A(2) (PLA(2)) is a key enzyme in the production of diverse mediators of inflammatory conditions, which possesses an open active pocket that is physicochemically compatible with a variety of small-molecule substrates and peptide inhibitors. Although various peptides and peptide analogues have been identified to have inhibitory activity against PLA(2) originated from animals and plants, only very few were designed for human secreted PLA(2) (hsPLA(2)), an attractive target of inflammatory arthritis. Considering that the catalytic domains of PLA(2) family members across different species are highly conserved in primary sequence, advanced structure, and biological function, in this study, we proposed a synthetic pipeline to implement structure-based grafting, mutation, and optimization of peptide ligands from the snake PLA(2)-peptide complex crystal structures into the active pocket of apo hsPLA(2) structure to computationally generate a large number of potential peptide inhibitors for hsPLA(2), and the hsPLA(2) inhibitory potency of few highly promising candidates arising from the theoretical analysis was determined. As might be expected, three peptides FLSFK, FLVYK, and FISYR showed relatively high inhibitory capability against hsPLA(2), and other three ALSYK, LVFYA, and KGAILGFM were also modestly potent as they can suppress the enzymatic activity with observable doses. Further, the designed peptide FLVYK with highest potency was carried out with structure-guided modification based on its atomic interactions with hsPLA(2) using the computationally modeled structure data, consequently resulting in a dual-point mutant ELIYK with significantly increased activity.