The 17th-seeded Russian was steadier and more explosive with her big groundstrokes in dismissing the 16th seed from Belarus and advancing to the last four of a major for the first time after four losses in the quarter-finals stage.
Boldly going for winners at every opportunity against the former world number one, Makarova pressured Azarenka to a dozen break points and cashed in twice in each set for her victory.
"I'm feeling amazing. Finally I'm in a semi-finals, finally I'm here," the 26-year-old Makarova, who is better known for her doubles exploits, told the Arthur Ashe Stadium crowd. "It's a great feeling."
Makarova has hoisted major trophies but always as part of a partnership, as winner of the French Open doubles in 2013 with Elena Vesnina and in mixed doubles at the 2012 US Open with Brazilian Bruno Soares.
The Russian, however, has thrived on her own racket in Flushing Meadows in the year's last grand slam by advancing without the loss of a set, eliminating seventh seed Eugenie Bouchard in overbearing heat in the process.
Makarova, who won her second career singles title at this year's Pattay City event in Thailand, will meet either two-time defending champion and top seed Serena Williams or 11th seed Flavia Pennetta of Italy for a berth in the final.
Azarenka, a two-times winner of the Australian Open, showed some rust from a season marred by foot and knee injures that forced her to withdraw from seven events and sent her ranking plunging from number two to 17th.
She also showed some frustration, earning a warning for racket abuse after being broken to fall behind 4-2 in the second set when her backhand tipped the net cord and landed just wide.
"Give credit to my opponent," the charismatic 24-year-old Belarussian told reporters in a hushed voice. "She played really well today. Am I disappointed? Yes, but I tried my best."
Azarenka's agent said on Twitter that she had suffered from a case of food poisoning on Tuesday but the 16th seed refused to comment.
"I'm not going to make any excuses," said Azarenka, who led their head-to-head series 3-2 but had won their previous two matches on hard court. "She deserves to win. She played much better than me today."
It was an entertaining match between two aggressive, power hitters but Makarova proved much steadier with her service game as she faced just three break points in the match, saving two, and took advantage of six double faults.
Azarenka drew first blood, breaking in the fifth game of the first set at 3-2 but Makarova broke right back, and broke again in the 10th game as she took advantage of loose groundstrokes from the Belarussian.
Makarova dominated the second set, keeping up the pressure after Azarenka saved four break points in the second game and two more in the fourth to remain level at 2-2.
The Russian finally broke through on Azarenka's next serve and clinched the quarter-final by breaking in the final game for an emphatic end to her 87-minute victory.
- Sports & Recreation