The Nigerian shot-stopper, widely regarded for her penalty-saving talent and commanding presence between the posts, proved she can also be a playmaker.
The win marked Southampton’s second Premier League victory of the season and provided a much-needed boost in their battle to avoid relegation.
Meanwhile, Nigerian youngster Ambrose Ochiegbo made his debut for Al-Kholood, coming on as a substitute in the 76th minute.
A 85th-minute winner from Carlos Romero sealed a historic win for the hosts, who absorbed wave after wave of Madrid pressure before striking on the counter-attack.
Heading into their 24th league game of the season, Southampton were desperate for a turnaround in their Premier League campaign.
Agbinone’s situation echoes that of former Crystal Palace academy graduate Victor Moses.
The Nigerian striker, who joined from Ligue 1 side Montpellier earlier in the week, was introduced in the 81st minute, replacing Suso.
Ligue 1 side Olympique Marseille has previously been linked with the Nigerian striker.
Unlike some of Nigeria’s traditional number nines, Akpom brings versatility to the attack. He can play as a center-forward, an attacking midfielder, or a right winger.
With the saga settled, Leverkusen boss Xabi Alonso expressed satisfaction with keeping the Nigerian forward.