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Bronchopulmonary dysplasia, the most prevalent chronic lung disease of prematurity, is often treated with glucocorticoids (GCs) such as dexamethasone (DEX), but their use is encumbered with several adverse somatic, metabolic, and neurologic effects. We previously reported that systemic delivery of the GC prodrug ciclesonide (CIC) in neonatal rats activated glucocorticoid receptor (GR) transcriptional responses in lung but did not trigger multiple adverse effects caused by DEX. To determine whether limited systemic metabolism of CIC was solely responsible for its enhanced safety profile, we treated neonatal rats with its active metabolite desisobutyryl-ciclesonide (Des-CIC). DEX but not Des-CIC caused a reduction in body weight as well as reduced insulin-like growth factor-1 serum levels and chronic hyperglycemia in neonatal rats. However, Des-CIC was as effective as DEX in reducing the expression of various bleomycin-induced proinflammatory cytokine mRNAs. In vitro studies with various cell types demonstrate the potent GR transactivation and transrepression activity of Des-CIC, although genome-wide transcriptomic analyses reveal differences in DEX vs. Des-CIC responses in neonatal rat lung and liver tissue. Des-CIC is a GR super-agonist as revealed by an in vitro coregulator peptide binding assay. In addition, molecular dynamics simulations revealed unique Des-CIC-dependent allosteric signaling pathways between specific residues in the GR ligand-binding domain and receptor surfaces interacting with coregulator peptides. Thus, Des-CIC is a potential novel selective GR modulator that could impart a favorable therapeutic index for CIC use for even modest durations of GC exposure which could have long-lasting adverse somatic, metabolic, or neurologic effects., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)