While Djokovic grimaced and growled as he played through the pain barrier to fight back from 0-4 down in the opening set, Rafa Nadal was all smiles after he launched his bid for a ninth consecutive Monte Carlo crown with a ruthless 6-1 6-2 win over Australian Marinko Matosevic.
Second seed Andy Murray also looked in fine form as he cruised to a 6-1 6-4 win over Edouard Roger-Vasselin.
World number one Djokovic, who sprained his ankle while on Davis Cup duty 10 days ago, made a late call to participate in the tournament which is held in his adopted home town and was relieved to have survived his first match on clay this season.
"I'm not 100 per cent because of my physical issue but I'm still in the draw. I live here. Everything's alright," Djokovic said in a courtside interview in French.
During a training session on Tuesday, Djokovic avoided putting too much pressure on his stricken right ankle but he did not have that luxury on Wednesday when Youzhny made him chase the ball around the court.
Once Djokovic levelled for 4-4, he relied on his greater weight of shot to see him through the tricky encounter.
Following an exchange of breaks in the third set, Djokovic broke decisively in the ninth game and sent Youzhny packing with an ace on match point.
Third-seed Nadal's outing was more straightforward as he returned from a month-long break to record his 43rd victory in a row at the principality against Matosevic .
The Spaniard, who is being more selective with his schedule this year after being out of action for seven months with knee problems following a shock second-round exit at Wimbledon last year, was loudly cheered by the packed crowd and was never seriously threatened by his Australian opponent.
Matosevic opened a 2-0 lead in the second set but Nadal reeled off the next six to set up a meeting with 16th seed Philipp Kohlschreiber of Germany.
"I played well at the beginning, with the right intensity, with no mistakes. I was trying to do the right things to find a good feeling on the ball, to find the right rhythm. And I think I did," Nadal said.
"I played to the right places, and that gave me confidence."
The world number five announced his comeback by winning three of his first four tournaments, including the Indian Wells Masters Series last month, and is favourite to continue his reign on the picturesque Centre Court that has been his stage since he first won the tournament in 2005.
Second seed Murray also had little trouble in reaching the last 16. After a nervy opening game when Roger-Vasselin held an early break point, Murray barely looked in trouble as he eased through the 6-1 6-4 to set up a third round clash with Stanislas Wawrinka.
The Swiss 13th seed was a 6-1 6-1 winner against Albert Montanes earlier in the day.
Tenth seed Nicolas Almagro became the first early casualty of the tournament as he lost 6-4 6-2 to Austria's Jurgen Melzer.
Fourth seed Tomas Berdych had to recover from a break down in each set to move past Spaniard Marcel Granollers 7-5 6-4.
Canadian 22-year-old Milos Raonic, seeded 12, failed to set up a big-serving clash with Juan Martin Del Potro when he was beaten by Finland's Jarkko Nieminen 6-3 1-6 7-6.
Results from the Monte Carlo Masters Men's Singles Round 2 matches:
1-Novak Djokovic (Serbia) beat Mikhail Youzhny (Russia) 4-6 6-1 6-4
3-Rafa Nadal (Spain) beat Marinko Matosevic (Australia) 6-1 6-2
4-Tomas Berdych (Czech Republic) beat Marcel Granollers (Spain) 7-5 6-4
9-Marin Cilic (Croatia) beat Kevin Anderson (South Africa) 6-2 6-3
Jarkko Nieminen (Finland) beat 12-Milos Raonic (Canada) 6-3 1-6 7-6(3)
13-Stanislas Wawrinka (Switzerland) beat Albert Montanes (Spain) 6-1 6-1
Fabio Fognini (Italy) beat Albert Ramos (Spain) 6-3 7-5
Florian Mayer (Germany) beat Roberto Bautista (Spain) 5-7 6-4 6-4
Jurgen Melzer (Austria) beat 10-Nicolas Almagro (Spain) 6-4 6-2