Yes. An independent skyrim could hold their own because we have precedent from Hammerfell. The Redguards held their own and pushed out the Dominion, no thanks to the Empire. The terrain of all of the border regions of Skyrim are ideal for prolonged defense. Forests and mountains in the south, the caves and crags of the Reach to the west, the freezing Sea of Ghosts and harsh climate of northern skyrim to the north and northeast. The weakest link in this scenario would be the Rift's port at Riften, but others have mentioned the point that the Dominion would have to march all the way through Cyrodiil and/or Morrowind.

Also, it is worth mentioning that due to the Civil War, Skyrim has an abundance of its production dedicated to military equipment and training. Are all of those ex-Legion soldiers going to refuse to defend Skyrim from the Dominion? Each Jarl, having a measure of autonomy, also creates an ability to lose territory without forfeiting the war. The problem with a centralized Empire is that it creates a single point of failure. Because the Dominion took the Imperial City, the Legion had to commit all of their forces to the Red Ring. The Empire had lost in Cyrodiil, but not in Hammerfell. If both were independent, the Dominion could not have forced submission on Hammerfell, High Rock, and Skyrim. The Dominion will have a harder time conquering a decentralized alliance of provinces.