City have won their last three games against Mauricio Pochettino's side but Guardiola is taking nothing for granted after Friday's draw, which also saw last year's beaten finalists Liverpool receive arguably the most favourable tie after being paired with Porto.
The first legs will be played on April 9-10, with the return games on April 16-17.
It means the two sides are set to play each other three times in just 11 days with Tottenham due to visit City's Etihad Stadium in the Premier League on the 20th of April.
The draw contained four English clubs for the first time since 2009 when Manchester United went on to reach the final in Rome.
City, chasing an unprecedented quadruple, beat Tottenham 1-0 at Wembley in October in the Premier League in their only meeting so far this season.
Liverpool will face Porto, a team the five-time champions beat in the last 16 last season.
City, who visit Swansea City in the FA Cup quarter-finals on Saturday, remain in the hunt to win four major trophies this season and those hopes will be boosted when star midfielder Kevin De Bruyne returns from a hamstring injury after the worldwide break.
Former Liverpool goalkeeper Chris Kirkland was delighted by the draw, telling Sky Sports News: "I'd prefer being at home for the second leg but I'm extremely happy".
City have already lifted the Carabao Cup this season. They will play Juventus, who destroyed another Spanish side, Atlético Madrid, who will host the final at the Wanda Metropolitano but won't be in it.