Sheikh Mohammed paid $2.5 million, the highest amount spent on a yearling at public auction in North America this year, for a colt by Tapit who is a half-brother to the 2016 Kentucky Derby winner Nyquist.
He also went to $2.15 million for a son of Medaglia d'Oro who is the first foal out of G1 winner Tara's Tango. Sheikh Mohammed's Darley stallion operation in Kentucky stands Nyquist and Medaglia d'Oro.
The price paid for the $2.5 million colt exceeds last year's $2.4 million September Sale top lot.
Monday marked the first of three sessions of the premier Book 1 of the September Sale with seven yearlings selling for $1 million or more including three who appeared in the ring in consecutive order.
Last year five horses sold for seven figures during the opening session.
Keeneland sold 107 yearlings for a total of $46,231,000 at an average of $432,065 and a median of $325,000.
Keeneland Vice President of Racing and Sales Bob Elliston said: "The results represent incredible trade and a deep buying bench that was active. The number I am most proud of today is the RNA rate, which was down almost six points to 29%."
Hinkle Farms consigned the session-topping colt, who is out of the winning Forestry mare Seeking Gabrielle.
At last year's September Sale, Hinkle Farms sold the Tapit colt's half-sister by War Front (now named Maria Rosa) to Godolphin for $1.75 million.
"Sheikh Mohammed is delighted to be here," said bloodstock agent Anthony Stroud, who signed the ticket for Monday's two high-selling colts.
"It is great for him to be back at Keeneland.
"The boss is just looking for attractive horses that will make good athletes and good racehorses, and that's why we're here"."
Nyquist, a September Sale graduate, is represented by his first crop of yearlings at this year's auction.
"We have been very impressed with the Nyquist yearlings as we have gone around looking at them," Stroud said. "That was one of the factors in this purchase."
Godolphin was the leading buyer with three purchases totaling $5,250,000. Its third acquisition of the day was a $600,000 Medaglia d'Oro colt out of stakes winner Wait Til Dawn from the family of Breeders' Cup winner Spain.
The $2.15 million Medaglia d'Oro colt is out of Tara's Tango, a daughter of Unbridled's Song who is a half-sister to G1 winner Visionaire and G3 winners Scarlet Strike and Madison's Luna.
Gainesway was the day's leading consignor by gross sales, selling 11 horses for $5,425,000.
The September Sale continues until September 22.