Atletico's defeat makes it consecutive seasons they have lost to a third-tier side in the cup after being knocked out by Cultural Leonesa 12 months ago.
The new format could suit Atletico Madrid, in single matches where game management is likely to be key and technical superiority has less time to win out than over the traditional 180 minutes.
With football on hold during the health crisis, Saul, 25, has launched Saldremos Juntos (We’ll get through this together), a campaign to boost Spain’s freelancers and small businesses whose livelihoods have been bludgeoned by the pause in activity.
Champions League: Atletico Madrid edge Liverpool with vintage defensive display; Erling Haaland helps Borussia Dortmund beat PSG
Liverpool play at home to Atletico on March 11 in the return leg at Anfield, where they produced an incredible 4-0 win over Barcelona in last year’s semi-final second leg after losing the first match 3-0.
Copa del Rey: Fans 'don’t deserve this,' says Atletico Madrid midfielder Saul Niguez after elimination at hands of Cultural Leonesa
Atletico, who are third in La Liga and into the last 16 of the Champions League, beat Barcelona 3-2 in the Spanish Super Cup earlier this month and held Real Madrid to a draw in the competition’s final before losing on penalties
The crucial moment in the game came when Real midfielder Federico Valverde deliberately fouled Alvaro Morata when he was through on goal in the 115th minute, avoiding a clear chance for Atletico but earning a straight red card
Atletico Madrid preview: With Joao Felix adding silk to Diego Simeone's steely side, new-look Atleti launch title challenge
Atletico Madrid finished the last two league seasons above Real and the same objective data that draws all the attention towards Real and Barcelona, begs everyone to consider Atletico as strong contenders for gold.
LaLiga: Atletico Madrid captain Diego Godin announces end of nine-year stint in Spanish capital in emotional press conference
Godin has been one of the best central defenders in the world under Atletico coach Diego Simeone, who attended an emotional press conference at the Wanda Metropolitano, along with several players and president Enrique Cerezo
LaLiga: Saul Niguez's solitary goal helps Atletico Madrid beat Leganes ahead of key Champions League clash against Juventus
Saul Niguez stepped up in Griezmann's absence and missed, but tucked in the rebound after Andriy Lunin could only push the ball back into his path
La Liga: Antoine Griezmann-led Atletico Madrid go level with Barcelona; Karim Benzema helps Real beat Rayo Vallecano
Karim Benzema's 13th-minute strike was enough for Real to move up to third on 29 points, two behind Barcelona and second-placed Atletico Madrid.
UEFA Nations League: Luis Enrique hails Spain's perfect start after 6-0 thrashing of World Cup finalists Croatia
Luis Enrique took charge after the humiliating exit to Russia at the World Cup had left Spain doubting the possession game that won them three consecutive major tournaments.
Spain's identity crisis looks to be well and truly over after Marco Asensio inspired a 6-0 thrashing of World Cup runners-up Croatia in the UEFA Nations League.
UEFA Nations League: England defender Kieran Trippier says team must not panic after defeat to Spain
Kieran Trippier says there is no reason for alarm after England slipped to their third consecutive defeat in their Nations League opener against Spain.
Super Cup: Diego Costa nets brace as Atletico Madrid battle past city rivals Real in extra time to claim title
Saul Niguez and Koke scored in extra time as Atletico Madrid fought back to beat city rivals Real Madrid 4-2 and win the UEFA Super Cup in Tallinn on Wednesday, as Julen Lopetegui got off to a losing start with the European champions.
Europa League: Arsene Wenger compares Arsenal's win over AC Milan to boxer fighting back after knockout
Arsene Wenger terms first-leg 2-0 victory over AC Milan as an important win after a 'nightmare week'.
La Liga: Lionel Messi produces moment of magic as solid Barcelona leave uninspired Atletico Madrid behind
In what was touted as a match between two of La Liga's most in-form men, Messi outshone Griezmann with ease, providing the decisive contribution that helped decide the tie.
La Liga: Surging Atletico Madrid visit stumbling Barcelona for crucial clash that could define title race
La Liga title race is well and truly back on and a poor February for Barcelona has ensured that the match with Atletico will be an evenly-fought contest.
Europa League: Arsenal stroll past Swedish minnows Ostersunds; Michy Batshuayi rescues Borussia Dortmund in first leg
Mesut Ozil scored as Arsenal eased to a 3-0 victory at Swedish minnows Ostersunds in the first leg of their Europa League, last-32 tie on Thursday, while Michy Batshuayi snatched Borussia Dortmund a dramatic win over Atalanta.
Last season's beaten semi-finalists Atletico Madrid and AS Monaco find themselves dumped out of Europe's premier footballing competition along with German giants Borussia Dortmund. Everybody's favourite underdogs were out without putting up a fight.
La Liga: Barcelona restore lead at top as Lionel Messi, Luis Suarez sink Villarreal; Atletico Madrid scrape past Betis
Barcelona restored their lead at the top of La Liga to five points as Luis Suarez and Lionel Messi struck in the final 20 minutes to edge out 10-man Villarreal 2-0 on Sunday.