From the south, exit I-5 on Exit 150. Go north on Eagle Valley Road through the town of Yoncalla. Just north of town, turn right on Halo Trail Road, then left on Old Applegate Road (after about a quarter mile). Applegate House is at the end of the road, perhaps another quarter mile.
From the north, take Exit 154. You will be going west on Elkhead Road, which will end at Eagle Valley Road after a few miles. Turn right on Eagle Valley Road and continue as in the directions above.