In this paper, HESH, which was a new set of amino acid descriptors including Hydrophobic, Electronic, Steric and Hydrogen bond contribution properties, were derived from multi-dimensional properties of 20 coded amino acids. The quantitative structure-activity relationship (QSAR) of 101 synthetic cationic antimicrobial polypeptides (CAMELs) was then characterized with HESH scales and studied by genetic algorithm-partial least square (GA-PLS) method. It was found that the robust QSAR model constructed with electronic and hydrophobic properties parameters of HESH descriptors was a better one. Through further analysis, electronic and hydrophobic properties of the 3rd, 6th, 7th, 11th and 12th residue of CAMELs sequence made high contribution to antimicrobial potencies. Based on this PLS model, a series of cationic antimicrobial peptides (AMPs), with relatively high antimicrobial activity was designed. Meanwhile, a robust QSAR model with favorable predictive capability for 34 antimicrobial peptides was constructed with HESH descriptors. The results showed that HESH descriptors had many obvious advantages, for it contains abundant information and its physico-chemical characteristics are clear and easily explained. The developed descriptors can be further expanded for the larger sets of biologically activities peptides and can serve as a useful quantitative tool for the rational design and discovery of antibiotics.