I just picked up a 78 F 150 it has the 300 I6 in it. The exhaust has headers on it at the moment but I think 1 end has rusted through. Would it be worth it to replace the header or just find a factory manifold?

 

I'm not a huge fan of headers especially when it's a daily driver for the rust reasons. You may want to look into using later model I6 split cast manifolds if the truck has dual exhaust (wrecking yards). If no dual's and if mine....
factory manifold.

 

I see I can use the newer EFI manifolds and possibly the Walker 45166 Y pipe? Will this fit my 78 F150 which is a 4x4 4spd.

 

I'm not sure of the differences between your 78 and my 84 aside the engines. Install the EFI manifolds while looking into local exhaust shops
(not a chain like Midas, etc.). 9 times out of 10, they can build the system from the manifolds back at the same cost or cheaper than you ordering the parts and then trying to configure them (it's a PITA). The only time they are hesitant or will not is if there is emissions elimination involved.
A local shop did my 302 (4x4) duals with glasspacks for $300.00 all in (emissions exempt) welded, not clamped 3 months ago. Great price, it sounds good and i couldn't be happier with it. Call around and let them know what you are doing, i'm sure they can quote reasonable prices. A friend of mine who as owned a local auto repair shop for 20 years even uses that local muffler shop because they can do it cheaper (parts and labor) than he can.