Goals from Marcus Thuram, Lautaro Martinez, Denzel Dumfries and Marko Arnautovic sealed the win that lifted Simone Inzaghi's side to 63 points, 10 clear of second-placed Juventus, who were shocked by Udinese on Monday.
Goals from Marcus Thuram and Davide Frattesi, along with a Hakan Calhanoglu penalty, propelled Inter Milan to a 3-0 victory over Lazio in the Italian Supercup semi-final on Friday, securing their place in the final against Napoli.
The Serie A season reaches the midway point this weekend and while no trophy is up for grabs just yet either Inter Milan or Juventus can claim the title of winter champions.
Inter are top with 45 points but the result gives second-placed Juventus, on 40, an opportunity to close the gap as they host AS Roma on Saturday. Genoa are 13th with 20.
Inter still lead the way in what is increasingly looking like a two-horse race for the title, with Juventus, two points behind, now matching them stride for stride.
Serie A champions Napoli host league leaders Inter Milan on Sunday, with the title defenders looking to show the title pretenders that they are not out of the Scudetto race just yet.
No financial details were disclosed, but Italian media reported that the 27-year-old has joined Simone Inzaghi's side for a fee of around 32 million euros ($34.94 million), signing a five-year contract.
Sky Sports said United will pay 51 million euros ($56.70 million) for the 27-year-old plus four million in add-ons.
The 35-year-old arrives in Milan after an eight-year spell at Juventus, which ended at the end of June when his contract expired.
Skriniar's last season was plagued by injuries as he missed over 20 games in all competitions with Inter, who finished third in the Italian top flight. Skriniar has been linked to a move to Ligue 1 champions Paris St Germain.
The 37-year-old, who played in Inter's Champions League final defeat by Manchester City earlier this month, has signed a two-year deal with the Istanbul-based club.
"There are many. Inter are a team used not only to defend. There is a belief that Italian teams only know how to defend, but Inter can do many other things," a relaxed Guardiola told reporters on Friday.
City will be favourites against the Italian side, a situation they also found themselves in against Chelsea in the final two years ago, only to surprisingly lose.
Pep Guardiola's side have wrapped up a fifth Premier League title in six seasons, beat Manchester United to win the FA Cup last weekend, and could be crowned European champions for the first time with victory over Inter in Istanbul.
"I am happy, because we won a cup that we wanted, to confirm what we did last season. Fiorentina are a quality team who caused us a lot of problems."
Inter grabbed two early goals through Edin Dzeko and Henrikh Mkhitaryan and will take a big advantage into the second leg back at the San Siro on Tuesday.
It will be Inter's first semi-final appearance since they won the European Cup for the third time in 2010, the last Italian Champions League triumph with Juventus losing the 2015 and 2017 finals.
Spezia struck through Daniel Maldini and M'Bala Nzola's penalty to beat Inter for the first time, with Romelu Lukaku's equaliser from the spot counting for nothing in the end.
Porto midfielder Otavio was sent off 12 minutes from time and Belgian striker Lukaku took full advantage to boost Inter's bid to qualify for the quarter-finals of Europe's premier club competition for the first time in 12 years.
The annual meeting between the Coppa Italia winners and Serie A champions was played at the King Fahd International Stadium in Riyadh, Saudi Arabia.