The Spaniard dropped just one game on his way to reaching the quarter-finals of a tournament at which he has been a losing finalist on three occasions.
Nadal raced out of the blocks by recording consecutive breaks against the world number 57, who got onto the scoreboard by serving to love to pull the first set back to 4-1.
Istomin had a break point in the next game on Nadal's serve as he briefly threatened to make the opener competitive, but the top seed held firm and then immediately broke to claim the set 6-1.
After saving two break points early on, the second set was even more comfortable for Nadal, as he broke all three times on the Istomin serve, and held to love on his own, to wrap up a 6-1 6-0 victory.
The 13-time Grand Slam champion will play Italian Fabio Fognini in the last eight.