I live in Lower Merion and work in Center City. I have been riding in Harleysville for 23 years, and have been doing the drive up there for 20 years from Center City on weeknights. 20 years is a long time to do that drive. It has not gotten any easier, and sometimes I want to pull my hair out. For instance, last night, I left my desk at 5:15 p.m. and got to the barn at 7:05 p.m. I was so tired that I took one look at the mud covered beast that is my horse and decided I would just give him a bath instead of riding. This is an oft-told tale in my life.
That said, from Manayunk, going up that way on the NE Extension or out West are your best bets. As the one poster above said, if you have to cut across the city to get to NJ from Manayunk, you are not going to have an easy time. The worst part of my ride west from Center City is the Schuylkill, specifically the stretch from the Art Museum to Conshohocken. If you start off in Manayunk, you cut out about 20-30 minutes of that nightmare that you would otherwise have to go through if you came out of Center City.
Welcome back, good luck in your search and feel free to PM me if you want any help.