It will be a long trip by car to get to SML from Venice, but I would think it would be the easier option. I would suggest that you plan a lunch stop in a town along the way. You will probably travel through Emilia-Romagna and could stop in Bologna, Parma, Modena or some other town for an amazing lunch - These are some amazing places just off the Autostrada route you would most likely follow.

I wouldn't go to the Milan Train Station and get a car there as the streets out of Milano are a bit confusing. Getting out of the Venice Airport or the Main Train Station with a rental car is very easy...

You should consider Lerici was your base. It is very charming, gorgeous views, white sand beaches and is very accessible (only 10 minutes to the autostrada although you'd never know it). There is a train station 12 minutes away in Sarzana and you can take the ferry boat to visit Portovenere and Le Cinque Terre. The drive from Venice is about 4 hours.