Scotland will face a “challenging” winter, he said, as flu and non-Covid respiratory viruses are set to make a comeback after lower levels in 2020 weakened population immunity.
And Covid cases are expected to rise in the next few weeks, as restrictions ease and schools return.
Mr Yousaf said that while he is “hopeful” a return to lockdown will not be necessary, he could not rule it out. “All it takes of course is a new variant to come from somewhere halfway across the world to make its way into Scotland,” he said.
From today social distancing will no longer be a legal requirement, and limits on numbers at social gatherings will be removed.
Some 1,240 new cases of Covid were reported on Sunday, while 360 people were in hospital with Covid and 40 people were in intensive care, and the Scottish Government has announced an extended flu vaccination scheme this winter in a bid to reduce the risk to the NHS.
It comes as hundreds of smaller pubs and restaurants along with nightclubs are set to open for the first time since March 2020.
Some venues were preparing to open for the first time from midnight on Sunday night, while others have planned major events on Monday.
But businesses and opposition politicians have pressed for more clarity on the new rules, after a week of back and forth following the First Minister’s announcement that Scotland would move beyond Level 0 as planned.
The Scottish Government confirmed on Friday that face coverings do not have to be worn in nightclubs or other hospitality settings when drinking, dining or dancing.
The face covering requirement is likely to remain in other settings until the end of February 2022.
Scottish Labour Covid Recovery spokesperson Jackie Baillie said on Sunday that the transition out of Level 0 had raised “more questions than answers”.
She said: “As restrictions lift, it is more important than ever that we have clear and consistent communication from the government - but so far we have been left with more questions than answers. Even on the most basic issues, people and businesses are in the dark.
"From their confused position of face coverings to their indecision on vaccine certificates, you get the feeling the SNP are making this up as they go along.
“The fact that the Health Secretary doesn’t seem confident that their plan out of lockdown is sustainable is all the more cause for alarm.”
Speaking on the BBC, Mr Yousaf said there was “no guarantee” on a future lockdown.
“All it takes of course is a new variant to come from somewhere halfway across the world to make its way into Scotland,” he said.
“And depending on how effective our vaccine is against it, that could make a big, big difference in terms of restrictions.”
Mr Yousaf added that Scotland is currently on a “positive trajectory,” and the successful vaccination of the most vulnerable in society will hopefully mean that a winter lockdown is not necessary.
However, winter will be “challenging”, he said, with a more severe than usual flu season and waves of other respiratory viruses expected.
Cases are also set to rise as restrictions ease.
“We would expect [a rise in cases] but of course we are continuing to vaccinate people which is the real positive,” he said.
“But that of course is why we’re keeping some mitigations absolutely in place.”
A Scottish Government spokesperson said the measures are currently set to last until the end of February.
“We are expecting this winter to bring a number of significant challenges. In order to ensure we are best placed to manage those pressures, the current regulations are scheduled to expire at the end of February,” they said.
“However, this will be reviewed every three weeks to ensure the precautions remain necessary and proportionate.”
Scottish Conservative chief whip Stephen Kerr accused the government of “moving the goalposts” on restrictions.
"Humza Yousaf needs to be clear about what comes next for people and jobs, which will help compliance and acknowledge the sacrifices made by so many, getting to where we are now,” he said.
"The SNP's shambolic messaging has left nightclubs and other businesses to make their own policies in the meantime.
"But that confusion can’t continue forever, and indefinite restrictions will hold back our recovery."
Nightclubs around the country have been preparing to reopen after 17 months.
While many will wait until the weekend for their first event, some were set to welcome revellers from midnight on Sunday.
One such venue, Sneaky Pete’s in Edinburgh, planned to be open from midnight until 5am.
Manager Nick Stewart said tickets had been fully booked in advance, but some space was left for walk-ins.
"We're so keen to see our music loving regulars come in to enjoy the DJs and the famous Sneaky Pete's atmosphere,” he said.
"We've got some tables seats, standing room too, and dancing is finally allowed!”
CC Blooms, Edinburgh's oldest gay bar and club, said that at the stroke of midnight tables would be cleared from the bar and dancing would begin.
Glasgow’s The Berkeley Suite told customers that “at the stroke of midnight” the doors would open again for the first time in almost 18 months.
"It’s hard to put into words how big this is, easy to write how excited we all are,” said a post on the club’s Facebook page.
"For the last 18 months, we have been (more or less) silent but finally, we’re able to open our doors, arms, hearts, and minds to you and some of our favourite DJ’s once again.”