Arriving Friday evening gives you two full days to see Rome at a relaxed pace, without trying to cram in every ruin and museum. This itinerary splits ancient Rome and the historic center across Saturday, then museums and Vatican City on Sunday, with plenty of room to wander and eat well in between.
Start the morning at the Colosseum, then take your time wandering through the adjoining Roman Forum and up onto Palatine Hill, where the views over the ancient city are worth lingering for. After a leisurely lunch, stroll past the Circus Maximus on your way toward the historic center, stopping at the Pantheon and tossing a coin into the Trevi Fountain. Round out the afternoon with a slow walk up the Spanish Steps before settling into dinner at a trattoria in the surrounding streets, where you can sit outside and watch the evening crowd go by.
Devote the morning to the Vatican Museums and the Sistine Chapel, then walk over to St. Peter's Basilica to take in the scale of the dome and square. In the afternoon, head to the Borghese Gallery if you have booked ahead, or wander the Capitoline Museums and the nearby Vittorio Emanuele II Monument for sweeping views over the city. Finish the weekend with an unhurried dinner near the Pantheon, then a final evening walk through the softly lit piazzas before heading back to pack.