From Massachusetts and Points South: 
I-95 North to Portsmouth Exit 7. Go right at the end of the ramp onto Market Street Extension. Drive one mile into downtown Portsmouth, and go left onto Bow Street. Follow Bow Street to its end. Go left onto State Street and cross the Memorial Bridge (U.S Route 1) into Maine. Immediately after the bridge (at the flag pole), make a sharp left onto Water Street. The Portsmouth Harbor Inn & Spa is the first building on the right. 

From Manchester Airport: 
101E to I-95N to Portsmouth Exit 7. Right at end of ramp onto Market Street Extension. Drive 9/10th mile into Portsmouth, take left at Bow Street and turn left at 2nd stop sign onto State Street. Go over Memorial Bridge (US-1) into Maine. Immediately after bridge (at the tall State of Maine flagpole), make a sharp left onto Water Street. The Inn is first building on right.

From the White Mountains and Interior New Hampshire:
Take the Spaulding Turnpike or Route 16 South to the Portsmouth Traffic Circle. Take the first right off the traffic circle to I-95 North. Take Exit 7 and proceed as described above in latter section of Massachusetts' directions.

From Maine:
Take I-95 South to Kittery, Exit 2 for Route 236. When you come off the exit, bear right and go straight to the Kittery Rotary. At the Kittery Rotary, pick up Route 1 South. You will be on Route 1 South approximately 1.5 miles. Just after the last set of lights, you will pass Kittery's Memorial Park on your left. The Portsmouth Harbor Inn and Spa is on your right just before the Memorial Bridge. Look for their sign and make a sharp right onto Water Street and into our parking area. If you have reached the bridge, you have gone too far and need to turn back.