Gabriel Jesus seemed to have struck an stoppage-time winner on Sunday (AEST) but a VAR (video assistant referee) check ruled Aymeric Laporte had handled the ball in the build-up.
For City, there were clear parallels with the UEFA Champions League quarter-final against Spurs in April, where Raheem Sterling's late winner was also cancelled by VAR as Mauricio Pochettino's side progressed on away goals.
Guardiola feels changes have to be made to the way VAR is used in football, particularly when it comes to applying updated rules such as hand ball and goalkeepers needing to stay on their lines for penalties.
"Deja vu. I thought we left that situation in Tottenham in the Champions League last season. But it is the same," Guardiola said.
"The referee and VAR disallow it. It's the second time [it's happened] - it's tough. It's honestly tough but it's the way it is.
"They have to fix it. The whistle inside matches now isn't quite clear. But they believe it's hands. Sometimes it's not — against [Spurs striker Fernando] Llorente in the Champions League.
"It was incredible it wasn't a penalty in the first half [when Erik Lamela tussled with Rodri in the box] but VAR said it wasn't and then at the end they did [disallow Jesus' goal]."
Expanding on his theme in a post-match news conference, Guardiola added: "It was hands for the Llorente goal in the quarter-finals in the Champions League.
"At [Wolverhampton Wanderers] it was hands, but [Andreas] Christensen in Liverpool v Chelsea [the UEFA Super Cup] was not hands, and then the goalkeepers must stay on their lines in penalties, and the last penalty Adrian was not on the line.
"Always we will have these types of situations, so that's what it is, accept it."
Harking back to the possible penalty incident involving Lamela and Rodri, Guardiola joked that VAR was taking a break during the incident.
"In the first half, the penalty? Ask the two referees around the corner. Then go to London to ask the VAR," he said.
"Go to London, ask the big bosses. I'm not VAR. They make an example to Premier League manages, which I saw. But what can I say?
"It was a penalty. Lamela goes over Rodri, and it was a penalty. Maybe in that moment, VAR was taking a coffee."
Guardiola and opposite number Pochettino were engrossed in conversation during the VAR ruling and the Spurs boss was more accepting of the technology's use.
"I'm very pleased with a point and but also knowing we need to improve," Pochettino said. "We are in a process where we need to improve in all areas and the team is going to improve step by step, but we need time.
"It was an unbelievable goal [Lucas's equaliser]. Always when you play a team like Manchester City, you have to play your best.
"We need to accept that [VAR]. I was a little bit critical of VAR but now we have to accept the rules. Now it benefits us. No doubt it won't benefit us at other times. It's a rule we need to accept."