The Italian has led the general classification after 13 of the 15 stages so far in the 2014 edition of the Tour to open up a gap of four minutes 37 seconds over Alejandro Valverde (Movistar).
With Chris Froome (Team Sky) and Alberto Contador (Tinkoff-Saxo) out through injury, Valverde is the Astana rider's nearest rival, with youngsters Romain Bardet (AG2R La Mondiale), Thibaut Pinot (FDJ.fr) and Tejay van Garderen (BMC Racing) completing the top five.
Tuesday sees the riders embark on the longest stage of the Tour this year as they travel 237.5 kilometres from Carcassonne to Bagneres-de-Luchon and into the Pyrenees.
Two further stages follow in the mountain range with Nibali ready for the challenge and confident that Astana have enough quality in their team to keep him, and his lead, safe.
"The stages coming up will be hard," he admitted. "We'll keep an eye on the breaks but it will be hard to leave a mark here.
"The objective will be to control the race and maintain the advantage I have. I have a significant gap and we'll have to know how to manage it. I need to stay calm, alert and close to my team.
"There could be strong riders who are a little further back who could get into breaks, and managing the race will be very difficult if that happens.
"You need to dose your energy in the last week and stay calm. This is still the Tour de France – every day is flat out, even if it might not always seem that way. There is a possible pitfall on every stage."