“Make yourself comfortable.”
A friend is coming over to have dinner with you in your home. You let her into the house. You need to go to the kitchen to check on the food, so you say this.
Make yourself comfortable.
This is a set expression that you tell people who are visiting your home. You say this so that the visitors will feel relaxed. (Although it's just a set expression, so people don't always relax just because you say this.) It's also often a signal that the guest should sit down if they want to.
You say "Make yourself comfortable" after your guest has entered your home and you're going to leave them alone for a few minutes. For example, you might say it when you go to another room to get something, when you get a telephone call, or when you go to talk to other guests.