Djokovic had never dropped a set in five previous meetings with Portugal's Sousa, but he surrendered a 4-1 lead in the opener and appeared under the weather before regrouping to break Sousa at 6-5.
Defending champion Jack Sock of the United States and fourth-seeded Alexander Zverev reached the third round in straight sets.
Raonic was scheduled to face Roger Federer in a second-round match on Wednesday.
Federer's only tournament victory in Bercy came in 2011.
He had issues with the same leg in the Wimbledon quarterfinals in a loss to American John Isner, and needed treatment on his back during his Round of 16 loss to Isner at the U.S. Open.
The Swiss star missed the event the past two years due to a combination of injury and selective scheduling.
"It wouldn´t have been good for me nor anyone to return to the court knowing that I wouldn´t be able to play my best".
The Spaniard has not revealed whether he will play in next week's ATP Tour Finals in London.
"I'm happy to play tomorrow". I mean, it's the only thing that you can feel when you see something like that and when you hear something like that. "I went and I did an ultrasound and MRI, and they found some kind of a lesion in the tricep".
"It's been a hard year for me in terms of injuries, and so I'd prefer to avoid doing anything drastic", he added.
"I can talk about a pain that bothers me overtime that I serve. So, for me, it was a very quick decision", the world No 3 said yesterday after arriving in France to play in the Paris Masters event.
Saudi Arabia has faced criticism following the recent death of journalist Jamal Khashoggi, a critic of the Saudi government who was killed at the country's consulate in Istanbul in October.
Both players this week have said they are assessing the situation and have yet to make a final decision over their participation.
Nishikori beat Frenchman Adrian Mannarino 7-5, 6-4 while Isner battled past Mikhail Kukushkin 6-3, 6-7 (2), 7-6 (1).