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Spinal cord injury (SCI) results in rapid muscle loss. The mechanisms of muscle atrophy have been well-described but there is limited information specific to SCI. Exogenous molecular interventions to slow muscle atrophy in severe-to-complete SCI have been relatively ineffective and the wide-ranging physiologic response to SCI requires the search for novel therapeutic targets. Connexin hemichannels (CxHC) allow non-selective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising pre-clinical results in slowing atrophy during sepsis and dysferlinopathy. We administered 50 mg/kg/d of boldine to spinal cord transected mice beginning 3 d post-injury. Tissue was collected 7 and 28 d post-SCI and the gastrocnemius was used for multiomic profiling. Boldine did not prevent body or muscle mass loss but attenuated SCI-induced changes in the abundance of proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 d post-SCI. SCI resulted in the differential expression of ~7,700 and ~2,000 genes at 7 and 28 d, respectively, compared to sham animals, with enrichment for pathways associated with ribosome biogenesis, translation and oxidative phosphorylation. Boldine altered the expression of ~150 genes at 7 d and ~110 genes at 28 d post-SCI. Methylation analyses highlighted distinct patterns at both 7 and 28 d following SCI both with and without boldine. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it preserved or attenuated SCI-induced changes across the metabolome, transcriptome and methylome.