The 29-year-old has been ruled out of Great Britain's Davis Cup quarter-final against France next weekend by the elbow injury that forced him to miss the Miami Open.
Team captain Smith has instead named Dan Evans, Kyle Edmund, Jamie Murray and Dom Inglot as the quartet who will travel to Rouen for the tie at the Kindarena from April 7-9.
Murray had hoped to pick up where he left off following a spectacular finish to last season but 2017 so far has not gone to plan.
After a gruelling winter training camp, Murray appeared jaded at the Australian Open and his fourth-round loss was followed by a diagnosis of shingles.
The Scot returned to action by winning a title in Dubai but then came the elbow injury, along with a virus, and his withdrawal from Miami.
Smith told Press Association Sport: "Obviously he's had a few things with shingles and now this.
"There's no doubt he played unbelievably well last year, especially the second half of the year, with so much tennis that maybe the effects of that are taking place.
"But it's bad luck as well isn't it. He's in great shape. He's a healthy guy, looks after himself as well as anybody."
— British Tennis (@BritishTennis) March 28, 2017
There has been no official update from the Murray camp yet on the nature of his injury or a timescale for recovery but his brother Jamie revealed at the weekend that he had a "tear" in the joint.
Murray's next tournament is scheduled to be the Monte-Carlo Masters, starting on April 16, or if that comes too soon then it is six weeks until the Madrid Open.
The good news is that Murray has a significant cushion at the top of the rankings thanks to Novak Djokovic's struggles but Roger Federer could soon be putting pressure on.
Smith learned the bad news in a series of messages with his close friend Murray.
"I've said before, and it is genuine, it's more important that he is healthy for the full season rather than trying to rush back for this, but it's not an option anyway," said Smith.
"He needs to take some time and get ready for Monte-Carlo. He's had his injuries before so he knows how to handle it.
"He'll be disappointed to miss this tie, it was certainly one he was looking to play in and he loves Davis Cup. But it's not to be."
France are also missing star names; with Gael Monfils injured, Richard Gasquet recovering from an appendix operation and Jo-Wilfried Tsonga spending time with his newborn son.
But they still have two top-25 players to call on in Lucas Pouille and Gilles Simon, while Nicolas Mahut and Pierre-Hugues Herbert are the reigning Wimbledon doubles champions.
The fact the tie is being played on clay would appear to reduce Britain's chances of victory further.
While Edmund is unusual in favouring the red stuff, and won two rubbers on it against Serbia last year, Evans has not played a match on clay for nearly two years.
The 26-year-old has made no secret of his dislike of the surface, and expressed that again in a sarcastic tweet after practising at Queen's Club on Tuesday.
But Smith sees no reason Evans cannot adapt his game, although he accepted doing so in time for this tie will be extremely difficult.
"It's about investing time into it," said the Scot. "Because he plays a bit differently, that's what causes the problems. It's not like you're putting Dan on a clay court and asking him to become more like a clay-courter, he'll have to adapt his game for it.
"But he's a good player, he's top 50 for a reason, therefore he can play good tennis on any surface.
"There's Monte-Carlo, there's Barcelona, there's Madrid, Rome and the French Open to play, so anything that happens over the next couple of weeks can help him for those as well. What a great way to get preparation."
Britain beat France at the same stage on their way to the title two years ago but, without Murray and on clay rather than grass, a repeat this time would be one of Britain's greatest victories.
Smith said: "They're the strongest in terms of quality and depth out of any of the nations. They're very difficult and obviously, on paper, for every single match they're going to have the highest-ranked players.
"All we can do, which will happen, is the guys will go out and fight hard and see what happens. We've had bigger ranking differentials to make up and the guys have done that but everyone's going to have to do it this time."