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.
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.