Goals from the prolific Diego Costa (22) and Koke (55) helped Atletico climb back above Barcelona as they fought back from a goal down to win at the San Mames.
Iker Muniain had put Bilbao a goal up inside six minutes after getting on the end of a long ball forward before lobbing the ball over Thibaut Courtois.
Costa clipped in the equaliser with his left foot midway through the first half and Koke's close-range header completed the comeback.
Aymeric Laporte was sent off late on for bringing down Costa - his second yellow card offence - but Atletico, who could not capitalise further, marched a point clear at the top.
Barcelona had temporarily claimed top spot after Messi calmly sent his spot-kick the other side of Espanyol goalkeeper Kiko Casilla, who was then sent off for handling another shot from Messi outside his area.
Defender Javi Lopez, who had given away the penalty, went in goal for the remaining eight minutes, but Barca were unable to take further advantage.
Barca then thought they should have been awarded a spot-kick when Pedro was felled in the area 11 minutes into the second half. Pedro later headed into the arms of Casilla from a corner - one of few chances from either side in a second period that was far more tranquil than the first.
Then the perfect opportunity to take the lead arrived, however - a penalty awarded for a handball against Lopez. Espanyol fiercely contested the decision, but Messi sent Casilla the wrong way to break the deadlock.
The goalkeeper managed to deny Messi soon after, but did so illegally and was sent off for handling the ball outside of his area.
Real Madrid maintained their own chase for the title with a 5-0 demolition of Rayo Vallecano at the Bernabeu in the final game of the evening.
Gareth Bale (68, 70) scored twice in two second-half minutes - the second of which was a fine run and finish which took him the full length of the field.
Cristiano Ronaldo opened the scoring on 15 minutes before Daniel Carvajal doubled the hosts lead 10 minutes after the break.
Bale tapped in Angel Di Maria's cross and then moments later charged from one box to the other, after Vallecano had earned a corner, before coolly slotting the ball past Ruben.
Sub Alvaro Morata (78) wrapped up the scoring with a powerful shot into the top corner as Real made sure they didn't lose any ground on their two rivals.
A late penalty from Nolito earned Celta Vigo a 1-0 victory over Sevilla which ended the visitors' six-match winning run in the Primera Division.
Unai Emery's side were on a high following a midweek success over leaders Real Madrid, but Celta ended that euphoria with the successful spot-kick three minutes from time.
A charge forward from Celta resulted in Federico Fazia giving away a penalty for a handball with just minutes left on the clock.
Nolito stepped up to take the spot-kick, slotting the ball into the bottom right corner.
It was a heavy blow for Sevilla and sparked a spell of late pressure to try and salvage something from the match.
However, Yoel ensured his side would keep all three points with two great saves to deny both Nicolas Pareja and Carlos Bacca in stoppage time.