We are planning to drive in May 2017 to Williamsburg Virginia from Scranton Pennsylvania. Is it better to go through 81 south/Harrisburg or through 476/ turnpike?
Any other advises? Google maps says it will take about a six hour and five minutes. Are any of you have done this trip before?
Thanks for any input.

IMO it is "better" to get up early and take the shortest route avoiding traffic.

I haven't made that specific trip, but I can't imagine that taking 476 would be better than taking 81.

Taking 476 would put you in the middle of the Phila metropolitan area and its traffic. Stick with 81 and pick up 95 south of DC.

Another possibility off I-81 at Harrisburg is I-83 through York and getting on I-95 near Tyson's Corner.
Stay out of the Philadelphia metro area.

Another possibility off I-81 at Harrisburg is I-83 through York and getting on I-95 near Tyson's Corner.

Not real wise to pick up I95 near Tysons Corner. If I95 is in the scheme, head farther south of metro DC to get on I95.

Depends on the day of the week,

Weekends the shortest route will be the fastest route.

Weekdays I try to get away from Washington as far as possible.

I have taken this route many times and frequently Harrisburg-Gettysburg-Frederick-Leesburg-Warrenton-Fredericksburg ( US 15 and 17 ) is just as fast and infinitely more pleasant.