Despite some third-party ownership issues, the Argentinian defender is expected to complete the move in this transfer window.
Spurs reinforced their greatest weakness with the signing of Swansea left-back Ben Davies; now they've turned their attention to central defence.
Jan Vertonghen is the undisputed starting left-centre-back, but with Younes Kaboul's fitness issues and Vlad Chiriches' unpredictable style of play, Spurs are one man short in defence.
Eric Dier was signed with an eye on the future while Michael Dawson has reportedly been on the verge of leaving since the transfer window opened. Perhaps characteristically, though, he is moving very slowly.
Musacchio's reputation has been growing rapidly in recent seasons since moving to Spain from Argentinian side River Plate in 2009.
The central defender was handed his debut at River by Daniel Passarella, a two-time World Cup-winning centre-back himself, he saw great promise in the then 16-year-old.
Initially joining Villarreal's B-team, Musacchio progressed and has been a regular starter for several seasons.
When Villarreal were relegated, the departures of Gonzalo Rodriguez and Carlos Marchena opened space in the squad and Musacchio took full advantage of the opportunity. He is so well thought of at Villarreal that he has often deputised as captain.
Initially deployed in a range of roles, including central midfield, Musacchio has settled on the right side of Villarreal's defence.
An old-fashioned centre-back, Musacchio's greatest strengths are his aggression and anticipation. He reads the game well and attacks the ball; he made 108 interceptions last season, according to Jay Jaffa's Goal.com report, which was more than any other player in La Liga.
When he takes possession, he seeks to distribute the ball quickly. Thanks to his experience playing in midfield, he is quite comfortable on the ball, but he does have a tendency to play hopeful long balls where possession could have otherwise been retained.
He could be described as impetuous and, despite his excellent record overall last season, he was responsible for some high-profile errors.
A little like John Terry, Musacchio throws his entire body into challenges. Desperate to win possession, his tackling style is a little haphazard, and he often takes the ball with a trailing leg having missed with his initial challenge.
He scored one of the most bizarre own-goals in recent La Liga history against Barcelona last season, though it would be harsh to blame him in this case.
At six feet tall, he is not a dominant physical presence nor does he jump particularly well.
If Musacchio does make the move to north London, his defensive partner will be crucial. Mercifully, Spurs have a perfectly suited counterpart in Jan Vertonghen.
The Belgian's poise makes him an excellent partner for the aggressive Musacchio. Ever available for a pass, Vertonghen should benefit from Musacchio's interceptions and quick disposal of possession.
Vertonghen suffered a disappointing second season in the Premier League but was outstanding in his first season.
Michael Dawson often suffered from Vertonghen's errors. Goals conceded against West Ham and Manchester City in particular resulted from the flawed nature of their partnership.
No such issues should exist with a Vertonghen-Musacchio axis. Musacchio's pace will allow Vertonghen to drive forward, safe in the knowledge that he is well covered. Equally, Vertonghen will be able to sweep behind Musacchio as the Argentinian attacks the ball.
Vertonghen and Musacchio should form an excellent centre-back partnership. Their qualities complement each other in a way that mirrors classic combinations of the past.
Consider Manchester United's Rio Ferdinand and Nemanja Vidic. Ferdinand's quality in possession and excellent reading of the game complemented Vidic's vicious, aggressive defending.
In the same way that Arsene Wenger protects against Per Mertesacker's obvious weaknesses, Mauricio Pochettino must recognise Musacchio's shortcomings in order to get the best out of him.
If Spurs do complete the reported £17 million signing of Mateo Musacchio, they will have one of the youngest defensive lines in the Premier League. Davies is 21, Kyle Walker is 24, Musacchio is 23 and Vertonghen is the elder statesman at 27.
Being able to consistently select the same back four is incredibly valuable. It builds combinations and makes each member more comfortable. The root of a strong team is so often a strong defence.
The signing of Mateo Musacchio will not, in itself, makes Spurs a Champions League-calibre team, but it will leave them with one of the most balanced and effective defensive lines in England.