Limb-girdle muscular dystrophy type R2 (LGMDR2, formerly 2B) is a late-onset, progressive muscle disease caused by mutations in the dysferlin gene which currently has no effective treatment. We have previously identified the replacement of healthy myofibers with intermuscular adipose tissue (IMAT) as a primary driver of disease onset and progression, making this process a therapeutic target for LGMDR2. We have also shown that the IMAT is caused by fibroadipogenic progenitors (FAPs), which accumulate excessively and aberrantly undergo adipogenic differentiation. Finding a therapeutic modality to target FAPs and prevent their adipogenic differentiation while maintaining their ability to help in muscle regeneration is crucial for the treatment of this disease. In this study we developed a two-tiered screening strategy to identify molecules that prevent IMAT accumulation. Firstly, small molecule inhibitors of adipogenesis were screened using a 96 well plate imaging assay to confirm their anti-adipogenic activity and determine the effective dose using primary human mesenchymal stem cells induced to differentiate in vitro. We then used freshly isolated FAPs from dysferlin-deficient (Bla/J) mice, which we have shown to differentiate spontaneously, to confirm efficacy in the context of LGMDR2. Our findings indicate that the molecules we tested exert their effects through various pathways, including HDAC inhibition, Wnt signaling, and metalloprotease inhibition. While some drugs prevented FAP differentiation, others inhibited adipogenesis at the cost of promoting alternative fibrogenic FAP fates. These inhibitors, along with the pathways they target, lay the groundwork for discovering additional drug candidates for treating LGMDR2 and other diseases linked to adipogenic degeneration of skeletal muscle.