In this paper, we present the development of a computer-based repurposing approach to identify FDA-approved drugs that are potentially able to interfere with irisin dimerization. It has been established that altered levels of irisin dimers are a pure hallmark of lipodystrophy (LD) syndromes. Accordingly, the identification of compounds capable of slowing down or precluding the irisin dimers’ formation could represent a valuable therapeutic strategy in LD. Combining several computational techniques, we identified five FDA-approved drugs with satisfactory computational scores (iohexol, XP score = −7.70 kcal/mol, SP score = −5.5 kcal/mol, ΔGbind = −61.47 kcal/mol, ΔGbind (average) = −60.71 kcal/mol; paromomycin, XP score = −7.23 kcal/mol, SP score = −6.18 kcal/mol, ΔGbind = −50.14 kcal/mol, ΔGbind (average) = −49.13 kcal/mol; zoledronate, XP score = −6.33 kcal/mol, SP score = −5.53 kcal/mol, ΔGbind = −32.38 kcal/mol, ΔGbind (average) = −29.42 kcal/mol; setmelanotide, XP score = −6.10 kcal/mol, SP score = −7.24 kcal/mol, ΔGbind = −56.87 kcal/mol, ΔGbind (average) = −62.41 kcal/mol; and theophylline, XP score = −5.17 kcal/mol, SP score = −5.55 kcal/mol, ΔGbind = −33.25 kcal/mol, ΔGbind (average) = −35.29 kcal/mol) that are potentially able to disrupt the dimerization of irisin. For this reason, they deserve further investigation to characterize them as irisin disruptors. Remarkably, the identification of drugs targeting this process can offer novel therapeutic opportunities for the treatment of LD. Furthermore, the identified drugs could provide a starting point for a repositioning approach, synthesizing novel analogs with improved efficacy and selectivity against the irisin dimerization process.