Please help! Will need to drive a rental car from EWR to 43rd St E between 2nd and 3rd ave.in Manhattan (Dropping car off at a rental car agency)on a Thursday morning, at about 9Am (flexible on time). Any advice on best directions/timing etc. Thanks

You are in for a lot of traffic driving into the city at the time of the day! It should be about a 30 minute drive, but it could take 2 hours...
Directions are straighforward.
From the airport look for signs to the NJ turnpike northbound.
Take the turnpike to exit 16 E, "lincoln tunnel"
Follow the signs to the Lincoln tunnel.
Go through the tunnel, and follow signs to 42 street exit.
Go east (should be making a right from the tunnel exit) about 10 avenues until 1st avenue.
(You do have to pass 2nd and 3rd avenues)
Turn left on 1st avenue, go up one block to 43rd street,
make a left and go one and a half more avenues until you are on 43rd between 2nd and 3rd.
How flexible are you on timing? Unless you go at least 2 hours earlier or later, the traffic (both into the city and inside the city) will be bad...

Why are you doing this? Would be much better idea to use public transportation to get into Manhattan. There are buses that go to Grand Central which is right near there and they can use bus lines through the tunnel.

I'm sorry to be grumpy, but you really need a better title on this post. Putting NYC in the title would probably get you more responses.

As long as your time is flexible I suggest you drop the car off around midnight and take public transport back to whereever. Or anytime between midnight & 4a.m.

Instead of driving, and not knowing where you are going with tolls and rental of the car, you should get a service car from Newark the price will be just about the same and you won't have to worry about directions it will be directly to your destination.

Carmel.com or dial7.com will give you a quote online. I think there are even discount online coupons for Carmel.

If you are not familiar with New York, really don't try and drive it.