Baggage check in Milan

How much time should I allow for baggage line in the morning? Also is the baggage check safe. We will have 2 rolling suitcases and small backpacks. Should the backpacks somehow be squeezed into our carry on luggage or are they safe left separate?

No one really knows the answer to your question regarding how much time it will take to deposit your luggage.
It all depends on how many others are there trying to deposit or retrieve their luggage.

Since you will be charged for each piece of luggage, you may want to place your backpacks into your luggage, if possible.
Your luggage should be safe but I'd suggest not leaving any valuables (passports, credit cards, money, etc..) in any of your luggage.

Have a great trip!

Edited to add...
I forgot to add this: Milano Centrale.it/station-services

I think we will plan to be back at the train station luggage line and hour before our train leaves at 4:15.
Does that seem reasonable or should we plan on even more time?

I’ve not left my luggage at this station before, so it’s hard to give you a definite answer.

You might arrive and be the only one there, or there may be a long queue of travelers.

Perhaps someone who has actually used this service will chime in with more information.

I've never seen big lines at left luggage facilities anywhere in Europe yet, but I can't vouch for Milan. This being said, a one hour buffer does err on the side of caution. I would stick with that, it is better to grab a drink at the station with your bags to pass the time than to miss your train.

We used the baggage check at Milano Centrale. The line was long for drop off but it was much shorter when we returned. It is going to depend on how many other people are doing the same thing. You should have no problem arriving and getting to the Duomo area on time.