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Interleukin‐17A (IL‐17A) is a pro‐inflammatory cytokine implicated in diverse autoimmune and inflammatory disorders such as psoriasis and Kawasaki disease. Mature IL‐17A is a homodimer that binds to the extracellular type‐III fibronectin D1:D2‐dual domain of its cognate IL‐17 receptor A (IL‐17RA). In this study, we systematically examined the structural basis, thermodynamics property, and dynamics behavior of IL‐17RA/IL‐17A interaction and computationally identified two continuous hotspot regions separately from different monomers of IL‐17A homodimer that contribute significantly to the interaction, namely I‐shaped and U‐shaped segments, thus rendered as a peptide‐mediated protein–protein interaction (PmPPI). Self‐inhibitory peptides (SIPs) are derived from the two segments to disrupt IL‐17RA/IL‐17A interaction by competitively rebinding to the IL‐17A‐binding pocket on IL‐17RA surface, which, however, only have a weak affinity and low specificity for IL‐17RA due to lack of the context support of intact IL‐17A protein, thus exhibiting a large flexibility and intrinsic disorder when splitting from the protein context and incurring a considerable entropy penalty when rebinding to IL‐17RA. The U‐shaped segment is further extended, mutated and stapled by a disulfide bridge across its two strands to obtain a number of double‐stranded cyclic SIPs, which are partially ordered and conformationally similar to their native status at IL‐17RA/IL‐17A complex interface. Experimental fluorescence polarization assays substantiate that the stapling can moderately or considerably improve the binding affinity of U‐shaped segment‐derived peptides by 2–5‐fold. In addition, computational structural modeling also reveals that the stapled peptides can bind in a similar mode with the native crystal conformation of U‐shaped segment in IL‐17RA pocket, where the disulfide bridge is out of the pocket for avoiding intervene of the peptide binding.