Having drawn their past three games in a row in all competitions - including their UEFA Europa League quarter-final first leg against 10-man Rangers in midweek - Athletic will have been eager to end that streak against Rayo.
However, Los Franjirrojos - themselves in the hunt for European qualification - were the first to threaten in Bilbao when Pedro Díaz headed wide of the post inside the opening minute.
At the other end, Mikel Jauregizar fired over before Álvaro García did the same for Rayo in an evenly-matched opening 25 minutes.
Around the half-hour mark, Gorka Guruzeta headed narrowly past the post as Athletic looked to assert their authority on the match. Nevertheless, it was the visitors who would strike the first blow of the encounter shortly after.
García’s poor effort on goal was never troubling Unai Simón between the Athletic sticks, but Dani Vivian could not avoid catching the striker’s thigh with his studs as he attempted to intervene.
Following a VAR review, a penalty was awarded and although Díaz’s spot-kick was saved by Simón, Pathé Ciss was on hand to bury the rebound and give his side the lead at the interval.
Athletic started the second half with intensity in search of an equaliser, and they were ultimately rewarded with a penalty of their own when Alfonso Espino tackled Maroan Sannadi to the ground off the ball.
Another VAR intervention was required before it was given, yet that didn’t stop substitute Oihan Sancet from keeping his composure as he sent Rayo goalkeeper Augusto Batalla the wrong way to level things up.
Perhaps with an eye on Thursday’s second leg, Ernesto Valverde rested some of his star players for this clash.
Ultimately, though, his substitutes had a decisive impact on the outcome as another second-half replacement completed the comeback. It was a lovely goal too, as Nico Williams caressed a curled strike into the corner from an angle.
Valverde’s opposite number Iñigo Pérez attempted to make some inspired changes himself, but his side were unable to recover from going behind, and their fate was sealed in injury time as Sancet curled a lovely effort into the corner from just outside the area.
The away team now trail sixth-placed Real Betis by six points with as many games remaining, having won just one of their last seven matches. Athletic, meanwhile, can look forward to the return leg against Rangers full of confidence.
Flashscore Man of the Match: Oihan Sancet (Athletic Club)