Where are you flying from, and when? This will determine the "best" flight to Italy.
Rome and Milan get nonstop flights from the US and Canada year-round. Bologna, Naples, and Venice get some flights from some cities "in season" (April or May to August or September). For other Italian cities, you have to make at least one change coming from North America.
Florence has a small airport; Bologna and Pisa have larger ones. Any of these airports can work for starting a trip in Tuscany. Florence is only 90 minutes from Rome by train, and about an extra hour from Rome FCO airport, so that can also work, particularly if you can get a nonstop flight, or if it's substantially cheaper than other options.
If you live in a city served by nonstop flights to Italy, that's easiest, although it may not be cheapest. If you live in a city with no nonstop flights to anywhere in Europe, you'll have to change in North America, so you'll be flying into one of the places above. And If you have nonstop service to Europe but not to Italy (for example, San Francisco or Seattle), then you can change in major European hubs for any city in Italy.
Look at Kayak or Google flights to see you options for you home city and your dates. Watch out for airport changes - for instance, your flight from the US lands at Paris CDG, but your flight to Italy departs from Paris Orly. Avoid these if at all possible!