After all Nadal last competed at a major at Wimbledon and had lost both singles matches that he contested this year as he returned from appendix surgery.
Nadal -- who also suffered from back and wrist injuries in 2014 -- cast doubt on his Australian Open participation just last week.
Youzhny, too, owned four victories over the 14-time grand slam champion.
But in a score that is sure to have his rivals taking note, the Spaniard crushed the former top-10 regular 6-3 6-2 6-2.
"Very positive result for me," Nadal told reporters. "I think very good start.
"Always before the first match you have the doubts, especially in this situation I'm arriving here. Never easy, but it was an important match for me. Was a comfortable victory that give me some confidence."
Nadal habitually lingers on court even when he wins in straight sets but he needed just one hour, 50 minutes to dispose of the veteran Russian.
He only faced one break point, dropped four points behind his first serve and struck 22 more winners than unforced errors.
"I think I returned well," said the 2014 finalist. "My return worked really well. The serve, too. I served, I think, the right way, with only one break point during the whole match. And in general I played with not many mistakes."
Nadal could face Roger Federer in the semifinals, and the Swiss began his charge with a 6-4 6-2 7-5 win over Yen-Hsun Lu.
Lu has upset the likes of Andy Murray, Andy Roddick and David Nalbandian in the past but he only really challenged the 17-time grand slam winner in the third set.
An attacking Federer -- appearing in a record extending 61st straight major -- approached the net more than 40 times, winning 70% of those points.
Nadal and Federer were joined in the second round by two-time grand slam winner Murray, although an outside contender for the women's draw, Ana Ivanovic, fell.
There was a time when many thought the former No. 1 would never return to the top 10 and top five but 2013 and 2014 saw the Serb re-climb the rankings. And last week, she extended Maria Sharapova to three sets in a final in Brisbane.
Her goal in 2015, she said, was to perform her best at the grand slams, yet Monday's 1-6 6-3 6-2 loss to Czech qualifier Lucie Hradecka means she still hasn't figured things out. Ivanovic heavily contributed to her downfall, hitting 10 double faults.
It's now only one grand slam quarterfinal for Ivanovic in her past nine attempts.
"It's really disappointing," Ivanovic told reporters. "It's probably the worst thing that could happen.
"I really have to now sit and work on few things and just maybe try to have a different approach to this kind of event and try to see what was lacking."
Ivanovic admitted to nerves prior to the encounter, as did third-seed Simona Halep ahead of her match against Karin Knapp.
But the fast-rising Halep overcame the nerves and eased past the Italian 6-3 6-2. Sharapova, bidding for a first major outside the French Open in seven years, defeated Petra Martic 6-4 6-1.
Halep's reward is a second-round clash with Aussie Jarmila Gajdosova, who snapped a long drought at her home major.
Having lost all nine of her previous matches in Melbourne, the big-serving Gajdosova ousted Halep's fellow Romanian Alexandra Dulgheru 6-3 6-4.
"I was talking to my coach and I told him I actually did feel like I won the Australian Open," Gajdosova said.
"It was just the first round but it's been such a long time coming. Not to be able to do it in your home Grand Slam was very devastating for me."
Later, there was more joy for Australia as two of its brightest prospects won five setters.
First Thanasi Kokkinakis upset 11th seed Ernests Gulbis 5-7 6-0 1-6 7-6 (2) 8-6. Kokkinakis -- who saved four match points in the fourth -- celebrated by doing a victory lap.
Not long after and past midnight in Melbourne, Nick Kyrgios -- Nadal's conqueror at Wimbledon -- edged Federico Delbonis 7-6 (2) 3-6 6-3 6-7 (5) 6-3.