The Australian "Pocket Rocket" had set off on Saturday wearing a grand tour points leader's jersey for the first time, but his fun ended after about an hour of riding on stage 8.
The star sprinter decided to abandon the race on the demanding 170km section from Foggia to Guardia Sanframondi, with his Lotto Soudal team reporting in a tweet that Ewan was suffering with knee pain.
Ewan's abandonment was not a huge surprise as he had never planned to complete the three-week race, with his sights set on also winning sprinters' stages at the Tour de France and the Vuelta a Espana.
"I need to do what's best in preparation for the Tour," Ewan said on Friday.
"This year so far has been very tough with the weather and a lot of guys legs are hurting a lot. I have to make sure I don't go so deep because if you do, it's hard to start again in the next Tour."
"Unfortunately, sprinters' legs don't recover in the same way that any other riders' do and if I finished the Giro now I would be dying for the next few months."
The 2021 Giro d'Italia continues as the riders tackle the climb from Castel di Sangro to Campo Felice - LIVE, FREE and in HD TONIGHT from 8:05pm AEST on SBS On Demand and 9:15pm AEST on SBS VICELAND.
