Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Current AF antiarrhythmic drugs have limited efficacy and carry the risk of ventricular pro-arrhythmia. GsMTx4, a mechanosensitive channel (MSC)-selective inhibitor, has been shown to suppress arrhythmias through the inhibition of stretch-activated channels (SACs) in the heart. The cost of synthesizing this peptide is a major obstacle to clinical use. Here, we studied two types of short peptides derived from GsMTx4 for their effects on a stretch-activated big potassium (BK) channel (SAKcaC) from the heart. Type I, a 17-residue peptide (referred to as Pept 01), showed comparable efficacy, whereas type II (i.e. Pept 02), a 10-residue peptide, exerted even more potent inhibitory efficacy on SAKcaC compared to GsMTx4. We identified through mutagenesis important sequences required for peptide functions. Additionally, molecular dynamics (MD) simulations revealed common structural features with a hydrophobic head followed by a positively charged protrusion that may be involved in peptide-channel/lipid interactions. Furthermore, we suggest that these short peptides may inhibit SAKcaC through a specific modification to the mechano-gate, as the inhibitory effects for both types of peptides were mostly abolished when tested with a mechano-insensitive channel variant (STREX-del) and a non-mechanosensitive BK (mSlo1) channel. These findings may offer an opportunity for the development of a new class of drugs in the treatment of cardiac arrhythmia generated by excitatory SACs in the heart..