By train
Como San Giovanni (from Milano Centrale) and Como Nord Lago (from Milano Cadorna) are both a short walk from the lake. Varenna-Esino is on the line to Tirano. Check times on the Trenord and Trenitalia websites.
From Milan, Lake Como is about an hour away by train: to Como from Milano Centrale or Cadorna, to Varenna from Milano Centrale. The best way to use a single day is to take the train and then a private boat from the lake: from Como, Grand Lake Como (6 hours, €1,350) reaches Bellagio and the villas.

Como San Giovanni (from Milano Centrale) and Como Nord Lago (from Milano Cadorna) are both a short walk from the lake. Varenna-Esino is on the line to Tirano. Check times on the Trenord and Trenitalia websites.
Morning train to Como, private boat from the Como pier at 10:00, villas and Bellagio, back by mid-afternoon and train to Milan. Or train to Varenna and a 2-hour tour of the central lake.
Coach tours from Milan include a short boat ride with many other people. A private boat for a family or friends often costs a similar total and you choose the times.
Every one of these tours passes it. Prices are for the whole boat.
Villa d'Este, Moltrasio, Laglio · Clooney's villa, Villa Pliniana
€600 per boat3 hoursVillas and BalbianelloVilla d'Este, Moltrasio, Laglio · Clooney's villa, Nesso waterfall
€800 per boat6 hoursGrand Lake ComoVilla d'Este, Moltrasio, Laglio · Clooney's villa, Nesso waterfall
€1,350 per boatFor a first visit, yes: with a private boat you see more in one day than in two by ferry.
At Como's public pier (a short walk from both stations) or at Varenna's pier.