Djokovic and Murray started the year as the top two ranked players, but poor performances along with injuries saw them drop in the rankings and eventually take time off after both last featured at Wimbledon in July.
Meanwhile, Nadal and Federer have benefited from the duo's absence in 2017 as they split the four Grand Slams between themselves. They have also won a combined 13 titles and currently share the top two places in the rankings.
With the impending returns of Djokovic and Murray, both of whom are confirmed for the 2018 Australian Open, many tennis fans are intrigued by how they will fare against the pair.
Safin, however, does not see Djokovic returning to the level that saw him achieve the rare feat of winning four straight Grand Slams last year.
"The next season Nadal and Federer will always be in the lead, while I do not see Djokovic able to return to very high levels, for him it will be a difficult situation," Safin told Live Tennis via Metro.
As for Murray, Safin believes the Briton will have his moments but will not win anything if he is facing a fully fit Nadal and Federer.
"Murray will have some highs and lows," Safin added. "But if Nadal and Federer do not [get] hurt, he will not be able to do anything."
It goes along with former British number one Greg Rusedski's belief that Murray is suffering from physical problems while Djokovic is suffering from a mental one.
"Murray, for me, it's not mental, it's physical," Rusedski said in October. "If the body comes back and the hip is fine and he can get himself physically fit again, and everything is firing, he will be in the mix to win majors again.
"Djokovic, for me, however, with the elbow injury – it's such a mental question mark. He was the best player bar none when he held all the four majors [at the same time] – which no player had done since Rod Laver.
"The fall from grace he has had has been incredible – that to me is mental and that can be more difficult [to overcome] sometimes than a physical injury."