[11][12] Nagatomo, wearing number 55, made his debut for Nerazzurri on 6 February 2011, replacing Wesley Sneijder in the Serie A match against Roma, won by Inter 5–3.

[14][15] On 6 March 2011, Nagatomo scored his first goal for Inter in the 5–2 trashing of Genoa on a Kharja assist with a swivel and a finish into the roof of the net.

[16] On 15 March, to show solidarity with his home country in light of the catastrophic earthquake and tsunami which took place the previous week he paraded the Japanese flag (with the writing "You'll Never Walk Alone", a chant of his former team in Tokyo) around the pitch during a Champions League match against Bayern Munich.

After the Serie A season was over, Inter Milan made an agreement with Cesena of making Yūto's move permanent in a cash plus player exchange deal.

Nagatomo started his second Inter Milan season by playing 62 minutes in the opening Serie A match against Palermo, which ended in a 4–3 away defeat.

[19] On 27 September 2011, Nagatomo provided an assist for Giampaolo Pazzini by nutmegging Aleksei Berezutski before driving the ball across goal during the 3–2 away win against CSKA Moscow in the second Champions League group stage.

[26] Nagatomo said that he had turned down a January 2016 offer from Premier League outfit Manchester United, stating that his intentions were to renew with Inter.

[28] During the 2016–17 season, he played 20 matches in all competitions, including 16 in league, 11 of them as starter, as Inter finished 7th in championship, was eliminated in the quarter-final of Coppa Italia by Lazio, and finished bottom in Europa League Group K.[29] Nagatomo improved his game at the start of 2017–18 season under new manager Luciano Spalletti, winning his place once again.

On 18 September 2021, Nagatomo make his first appearance for the club against Yokohama FC for the time since leaving for Europe 10 years ago.

He featured in every game Japan played in the competition and helped them defeat Australia in the final, thus earning his first international honour.

He was included in Alberto Zaccheroni's 23-man Japan squad for the 2013 FIFA Confederations Cup where he featured in the three games before they were eliminated in the group stage.

Nagatomo earned his 100th international cap on 10 November 2017 by captaining his side in the 1–3 friendly loss to Brazil at Stade Pierre-Mauroy, Lille.

Both of them appeared in the Captain Tsubasa Olympics special which, aired as part of the annual Jikan Terebi Nihon no Sport wa Tsuyo in November 2019.