Introduction: The coupling and timing of pro‐ and anti‐inflammatory processes in skeletal muscle injury is poorly understood. We investigated the temporal response and regulated processes of extracellular signal–regulated kinases 1 and 2 (ERK1/2), p38, and IkappaB kinase (IKK) α/β signaling pathways after traumatic injury. Methods: Traumatic freeze injury was delivered to the tibialis anterior (TA) muscle in C57BL/6J mice, and injured and uninjured TA muscles were analyzed 3–72 h into the recovery period. Results: Significant increases in pro‐inflammatory cytokine transcription accompanied IKKβ phosphorylation, robust ERK pathway activation, and reduced heat shock protein (Hsp) protein expression at 3–24 h. At 24 h, ERK activation was abolished concomitantly with a significant increase in mitogen‐activated protein kinase phosphatase‐1 (MKP‐1). After 24 h, cytokine transcription along with ERK1/2 and IKKβ phosphorylation remained suppressed, whereas Hsp protein expression rose to significant levels by 72 h and associated with IKKβ. Conclusions: Results indicate a bimodal regulation of ERK1/2 in acute inflammation in which it is supportive from 3 to 24 h, and suppressive from 24 to 72 h. Muscle Nerve, 2012