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<i>Staphylococcus hyicus</i> is recognized as a leading pathogen of exudative epidermitis in modern swine industry. Antimicrobial peptides are attractive candidates for development as potential therapeutics to combat the serious threats of the resistance of <i>S. hyicus</i>. In this study, a series of derivatives were designed based on the NZ2114 template with the aim of obtaining peptides with more potent antimicrobial activity through changing net positive charge or hydrophobicity. Among them, a variant designated as NZL was highly expressed in <i>Pichia pastoris</i> (<i>P. pastoris</i>) with total secreted protein of 1505 mg/L in a 5-L fermenter and exhibited enhanced antimicrobial activity relative to parent peptide NZ2114. Additionally, NZL could kill over 99% of <i>S. hyicus</i> NCTC10350 in vitro within 8 h and in Hacat cells. The results of membrane permeabilization assay, morphological observations, peptide localization assay showed that NZL had potent activity against <i>S. hyicus</i>, which maybe kill <i>S. hyicus</i> through action on the cell wall. NZL also showed an effective therapy in a mouse peritonitis model caused by <i>S. hyicus</i>, superior to NZ2114 or ceftriaxone. Overall, these findings can contribute to explore a novel potential candidate against <i>S. hyicus</i> infections.