It will work. TOO WELL. 25-06 is WAY too big for squirrels. It's more of a deer, antelope, and coyote caliber. If you want to hunt squirrels then may I suggest a 22 lr with 36-40 grain copper plated hollow points(solid points work too) an I prefer headshots only. Doesn't ruin any meat with headshots. If you use a 2506 on a squirrel there wont be a squirrel left. Just a bit of hair and hide will be all that's left.