The Blues headed into a meeting with Nuno’s side at the Etihad Stadium expected to close the gap on leaders Liverpool.
That advantage still stands at eight points, though, after a stunning brace from Adama Traore.
Wolves kept City out for 80 minutes before staging a remarkable surge past the finishing post.
Guardiola could only watch on stunned as his team suffered another untimely stumble in the defence of their English top-flight crown.
He had only previously seen his side draw a Premier League blank on home soil on three previous occasions.
Stoke, Manchester United and Huddersfield were, however, all contained to take something from those games.
City have now suffered a first Etihad league defeat to nil under their Catalan coach.
United were the last opponents to achieve that feat, but their derby success came towards the end of Manuel Pellegrini’s reign on the opposite side of Manchester.
0 - Manchester City have lost a @premierleague match at the Etihad Stadium without scoring for the first since March 2016 against Man Utd (0-1), with Manuel Pellegrini in charge. Stunned. #MCIWOL pic.twitter.com/aa1iXqRMVt— OptaJoe (@OptaJoe) October 6, 2019
Wolves boss Nuno has proved to be a serious thorn in Guardiola’s side in recent years.
The City boss boasts just one win over a Portuguese tactician calling the shots at Molineux.
In fact, only Ronald Koeman and current Liverpool manager Jurgen Klopp have better records.
25% - Pep Guardiola has a 25% win rate in all competitions against Nuno Espirito Santo (1/4); only against Ronald Koeman (0%) and Jurgen Klopp (22%) does he have a worse win rate as Man City manager (min 3 games). Perplexed. #MCIWOL pic.twitter.com/ODUGhT9ELG— OptaJoe (@OptaJoe) October 6, 2019
Wolves, though, have shown since returning to the Premier League that they are more than a match for the established elite.
They have shown no fear in meetings with the so-called ‘big six’ and have collected plenty of points as a result.
A slow start was suffered in the current campaign, but they are now very much up and running at home and abroad.
Wolves head into the international break in buoyant mood, but City have plenty of questions to answer.
They now have two weeks to mull over their latest setback and piece together a plan for closing the gap which separates them from table-topping Liverpool.
They were able to haul in the Reds last season, but know they face a big ask to do that again in 2019-20 after already seeing eight points slip through their grasp in eight games.