AC Milan slipped to their first defeat under Ruben Amorim with a 2-0 home loss to Benfica as the Europa League got under way on Wednesday, while Sunderland won on their return to Europe after a 53-year absence.
Seven-time European champions Milan had won two and drawn two of their opening four Serie A games, but were given a reality check by Benfica on the opening day of the Europa League league phase.
Milan were profligate in front of goal and were made to pay by the visitors, who maintained their unbeaten start to the season.
Benfica, who lost to Milan in the 1963 and 1990 European Cup finals, were able to enjoy their first-ever win over the Italian giants.
Marco Silva's side grabbed a 16th-minute lead through a superb individual goal from Dodi Lukebakio, as the Belgian cut inside from the right and unleashed a left-footed drive into the far bottom corner.
The Portuguese giants extended their advantage eight minutes after the interval when Jakub Kaminski slammed in Souffian El Karouani's left-wing cross.
Regis Le Bris's Sunderland clinched a 1-0 victory over AZ Alkmaar at a raucous Stadium of Light in their first European match since the Cup Winners' Cup second round in 1973.
Sunderland were the stronger team in the first half but failed to take their chances, with Enzo Le Fee going closest when he struck the post.
The Black Cats were awarded a penalty 20 minutes after the restart for Weslley Patati's foul on Le Fee.
The Frenchman, who had a penalty saved by David Raya in Saturday's Premier League loss to Arsenal, stepped up to slot the spot-kick into the corner.
Sunderland were indebted to goalkeeper Robin Roefs when he made an excellent save to deny AZ attacker Valdemar Byskov an equaliser in the 81st minute.
Lyon put some of the disappointment of their dramatic Champions League play-off loss to Fenerbahce behind them with a 2-1 victory at Anderlecht.
The visitors quickly took control in Brussels as Noah Nartey put them in front after less than eight minutes.
Keito Nakamura's deflected strike doubled the lead midway through the first half and gave the Japan winger his first Lyon goal since signing from Reims.
Anderlecht pulled one back through teenage striker Mihajlo Cvetkovic's header after half-time, but Lyon held on under severe pressure.
Bayer Leverkusen saw off spirited Slovenian champions Celje 2-0 in Germany.
Leverkusen forged ahead when Celje midfielder Svit Seslar put through his own net in the 15th minute and Argentina international Facundo Medina made the points safe with 16 minutes remaining.
Elsewhere, Olympiacos came from behind to beat Poland's Jagiellonia 2-1, while Sparta Prague brushed aside Ararat 4-1 in Armenia and Cypriots Omonia edged out Celta Vigo.