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A second-minute strike by Danny Ings was enough for Southampton to register a 1-0 victory over Liverpool at St Mary's on Monday.
The teamsheet showed that Jurgen Klopp handed Thiago Alcantara his first start since October, while Alex Oxlade-Chamberlain was also included in the starting line-up.
Liverpool, however, had a makeshift defence as their defensive crisis meant that traditional midfielders Fabinho and Jordan Henderson started as central defensive partners.
It took just 111 seconds for their unfamiliarity with the role to be exposed, as the Liverpool defence was caught out by a James Ward-Prowse free-kick, allowing Ings to open the scoring with a deft finish.
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The goal was his 50th in 124 Premier League appearances and was also the earliest he had scored in the competition.
A hamstring injury sustained to Moussa Djenepo on the half-hour mark forced the hosts into making a substitution. Other than that, it was a fairly comfortable first half for the Saints.
Liverpool expectedly upped the ante in the second half as they tried to force an equaliser. However, for all their possession, the defending champions were painfully short of quality and did not register a shot on target until the 75th minute.
Yan Valery had a late chance cleared off the line by Henderson. However, despite some sustained pressure in the dying embers of the game, Southampton held on to register a first victory over Liverpool since coming from two goals down to win 3-2 in 2016.
An emotional Ralph Hasenhuttl could not hold back the tears at full-time as his side became the first club in history to beat all seven winners of the Premier League in the season following their title win.
Up next for the Saints will be the visit of Shrewsbury Town in the FA Cup on Saturday, while Liverpool will travel to Villa Park to take on Aston Villa a day before.
Here are five talking points from the fixture.
#5 Poor run of form continues for Liverpool
Having ended 2019 with consecutive disappointing draws to West Brom and Newcastle, Liverpool would have been looking to kickstart the new year on a winning note. However, that was not the case.
This defeat means that the Reds have lost two games from their opening 17 matches of the season.
Furthermore, Liverpool have already dropped points in eight of their 17 games to date. At this same stage last season, they had dropped points just once.
Of course, the congested nature of the campaign, coupled with several injury concerns, have played a part in the drop-off in performance. However, if Liverpool are to successfully retain their title, Klopp has to find a way to arrest this poor run of form.
#4 Southampton continue to defy expectations
At the start of the season, few would have tipped Southampton to be among the challengers for a European spot. Surprisingly, with almost half of the season gone, the Saints are in with a shout for a top-six finish.
Positive results have already been registered against the likes of Everton, Chelsea, and Arsenal, while they were unlucky in their 3-2 defeat to Manchester United. The biggest scalp so far is, however, Liverpool.
This is a far cry from the side that was walloped 5-2 by Tottenham Hotspur on the second day of the season.
At one point in the campaign, Southampton topped the table but a run of four games without a win had seen them slide down to mid-table.
This victory pushes Southampton up to sixth on the table, just four points behind table-toppers Liverpool. If the Saints can keep their fine run going, they could be firmly placed to gatecrash the top six.
#3 Trent-Alexander Arnold has a game to forget for Liverpool
Over the last three years, Trent-Alexander Arnold has proved his mettle in the Liverpool squad.
The academy graduate has played a key role in the successes enjoyed by the team and is living the dream with his boyhood club.
His combination with Andrew Robertson on the Liverpool flank is priceless, and his attacking impetus has suggested a more advanced role later in his career.
However, the England international was way off the pace against Southampton and put out arguably his worst performance in a Liverpool shirt.
He failed to effectively deal with Ward-Prowse's cross in the build-up to the goal, and this set the pace for the game.
Alexander-Arnold was lacking his usual verve and drive, while he offered next to nothing in an attacking sense.
In total, the 22-year-old gave away possession a staggering 38 times - 10 more than any other Liverpool player - as well as the highest in the league this season.
It came as no major surprise when Jurgen Klopp substituted him for James Milner in the 77th minute, and fans of the club would be hoping that this game was a one-off.
#2 Title race blown wide open
Two of the last three Premier League campaigns had a runaway leader who effectively wrapped up the title by Christmas, while Liverpool and Manchester City engaged in a two-horse race far beyond the rest of the chasing pack in 2019.
This season has, however, been different, as a combination of several factors has given us one of the most dynamic campaigns in recent memory.
With 17 matchdays gone, the table is a clustered zone, and all it takes is one negative result for a team to spiral down the standings.
Despite this defeat, Liverpool still lead the way on goal difference but their position at the top is extremely precarious. They could lose in a fortnight when they trade tackles with a resurgent Manchester United, who have a game in hand.
The Red Devils have impressed in recent weeks, making their 6-1 loss to Tottenham Hotspur earlier in the season look like a distant nightmare.
Further down in fifth place lies Manchester City, who are just four points behind the champions with two games in hand. If the Cityzens can win their outstanding fixtures, the top of the table could well look very different in the next few weeks.
Even Aston Villa in 8th are not left out, as just seven points separate them from Liverpool, with the Villans holding a two-game deficit.
In essence, just seven points separate the top 10 teams on the table, with Southampton's victory over Liverpool helping to open the title race even further.
The Premier League prides itself on being the most competitive league in the world. In this most unique of seasons, that is proving to be the case.
#1 Impressive Danny Ings haunts Liverpool
Danny Ings was arguably the revelation of the Premier League last season and ended the campaign with a respectable tally of 22 league goals.
The 28-year-old had initially spent time with Liverpool but his spell at Anfield was mired by injuries, restricting him to just 14 Premier League appearances in three seasons.
While his talent might never have been in doubt, the arrival of Ralph Hasenhuttl at St Mary's has helped the England international develop into one of the most complete forwards in the league.
Since the German's appointment in 2018, the former Burnley man has been directly involved in 39 goals, scoring 31 and assisting eight.
His calmly lobbed goal with his weaker foot against Liverpool bore the hallmarks of a great striker and underlined his growing confidence in his own abilities.
It was his 7th goal from 13 Premier League appearances this season. In this form, he could well fire Southampton to the upper echelons of the league table.
