Trailing 2-4 in the first set, five-times Grand Slam winner Sharapova tightened control of her booming groundstrokes to break back, then steamrolled to victory in her return to Flushing Meadows after missing last year's event with a shoulder injury.
"It was tough missing this court last year," the French Open champion told the crowd in an on-court interview after improving her US Open night record to 17-0. "To be back here you realise how meaningful it is to keep working."
Sharapova, the 2006 US champion, will next meet Romania's Alexandra Dulgheru, a straight sets winner over Czech Kristyna Pliskova.
Second seed Halep lost a first-set tiebreak to US debutante Danielle Collins before claiming victory.
Halep survived a scare in the tournament's opening match on stadium court before overtaking Collins 6-7 (2) 6-1 6-2.
The 22-year-old Romanian, a finalist at the French Open, admitted to a case of nerves in being thrust onto the big stage as the opening act of the season's last Grand Slam.
"She played a tough match, I want to congratulate her," Halep said about her 20-year-old opponent, who was given a wild card for winning the US college championship.
"The first set I was a little bit nervous. This court is huge.
"I have to enjoy it, but it's not easy. Everybody is telling me I have chances to win this title."
She moves on to face Slovakian Jana Cepelova, a 2-6 7-5 6-1 winner over Spain's Maria-Teresa Torro-Flor, in the second round of the season's last Grand Slam.
First the 43-year-old Japanese player and later 34-year-old Williams dipped, ducked and danced away before ballgirls helped usher the determined bees off the baseline.
When finally left to play tennis on sun-bathed Arthur Ashe Stadium court, seven-time Grand Slam singles winner Williams stung Date-Krumm 2-6 6-3 6-3 to advance.
Asked about who presented the peskier test in the two-hour match, Williams said: "The bee was a challenge but easily the answer is Kimiko.
"The way she hits the ball is like no one else on tour and it's never easy to get a rhythm with her, and all our matches have been tough. So I'm happy to have pulled it out."
US Open results
5-Maria Sharapova (Russia) beat Maria Kirilenko (Russia) 6-4 6-0
19-Venus Williams (U.S.) beat Kimiko Date-Krumm (Japan) 2-6 6-3 6-3
6-Angelique Kerber (Germany) beat Ksenia Pervak (Russia) 6-2 3-6 7-5
Alla Kudryavtseva (Russia) beat Duan Yingying (China) 2-6 6-2 6-4
31-Kurumi Nara (Japan) beat Aleksandra Wozniak (Canada) 6-2 6-1
21-Sloane Stephens (U.S.) beat Annika Beck (Germany) 6-0 6-3
Johanna Larsson (Sweden) beat Virginie Razzano (France) 6-0 6-0
Tsvetana Pironkova (Bulgaria) beat Karin Knapp (Italy) 6-4 6-3
9-Jelena Jankovic (Serbia) beat Bojana Jovanovski (Serbia) 6-2 6-3
14-Lucie Safarova (Czech Republic) beat Timea Babos (Hungary) 6-4 7-5
Zheng Saisai (China) beat Stefanie Voegele (Switzerland) 1-6 6-2 6-2
Daniela Hantuchova (Slovakia) beat Romina Oprandi (Switzerland) 4-6 6-2 6-3
22-Alize Cornet (France) beat Amandine Hesse (France) 6-1 6-2
28-Roberta Vinci (Italy) beat Paula Ormaechea (Argentina) 6-3 6-3
Irina Begu (Romania) beat Silvia Soler Espinosa (Spain) 7-6(4) 6-3
Peng Shuai (China) beat Zheng Jie (China) 6-3 6-3
4-Agnieszka Radwanska (Poland) beat Sharon Fichman (Canada) 6-1 6-0
Alexandra Dulgheru (Romania) beat Kristyna Pliskova (Czech Republic) 6-3 6-4
Madison Brengle (U.S.) beat Julia Glushko (Israel) 6-3 6-2
26-Sabine Lisicki (Germany) beat Francoise Abanda (Canada) 6-3 7-5
18-Andrea Petkovic (Germany) beat Ons Jabeur (Tunisia) 7-6(7) 1-6 6-3
Monica Puig (Puerto Rico) beat Tereza Smitkova (Czech Republic) 3-6 6-3 6-3
Aliaksandra Sasnovich (Belarus) beat Anna Karolina Schmiedlova (Slovakia) 6-4 6-3
10-Caroline Wozniacki (Denmark) beat Magdalena Rybarikova (Slovakia) 6-1 3-6 2-0 (Rybarikova retired)
13-Sara Errani (Italy) beat Kirsten Flipkens (Belgium) 6-1 7-5
Anastasia Rodionova (Australia) beat Camila Giorgi (Italy) 1-6 7-5 6-3
Timea Bacsinszky (Switzerland) beat Kiki Bertens (Netherlands) 6-7(7) 4-3 (Bertens retired)
Mirjana Lucic-Baroni (Croatia) beat 25-Garbine Muguruza Blanco (Spain) 6-3 7-6(4)
Shahar Peer (Israel) beat Johanna Konta (Britain) 6-2 6-3
Jana Cepelova (Slovakia) beat Maria Teresa Torro (Spain) 2-6 7-5 6-1
2-Simona Halep (Romania) beat Danielle Collins (U.S.) 6-7(2) 6-1 6-2
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