While most mammals shed their hair and skin either continuously or seasonally, northern elephant seals (Mirounga angustirostris) undergo an annual catastrophic molt, in which they shed their entire fur and underlying skin layer in the span of just three weeks. Due to the energetic and thermoregulatory constraints of molting and the large distances between their coastal rookeries and foraging grounds, elephant seals must remain on land and fast for the duration of their molt. Previous studies of molting northern elephant seals have examined endocrine and metabolic adjustments to fasting, but not the molecular processes underlying molting. We examined changes in the skin and underlying blubber proteomes during molting to provide a more in-depth understanding of the cellular mechanisms enabling rapid skin shedding and regeneration in this marine mammal. Shotgun proteome sequencing by LC-MS/MS identified 48,078 peptides and 755 protein groups in skin and blubber that were associated with proteasome degradation, gluconeogenesis, and the Hippo cell signaling pathway. Label-free quantification and differential protein expression analyses identified 191 and 360 proteins that were differentially expressed over molting in the skin and blubber. Proteins upregulated in late molt skin included those associated with inflammation, amino acid synthesis, and angiogenesis. Proteins upregulated over molting in blubber included those associated with fat catabolism and fructose metabolism. This suggests that rapid skin regeneration involves intensive protein synthesis and increased vascularization that may be supported by fatty acid metabolism from underlying blubber tissue. These data provide insights into molecular mechanisms that govern unusually rapid skin regeneration in mammals, which may further understanding of disorders affecting the skin and hair of humans and other mammals.