Stepanek, ranked 50th in the world, was broken only once and did not double fault but needed nearly two hours to defeat the Uzbek.
Hewitt will try for his 600th career victory in a second round encounter against South African Kevin Anderson, who has been a losing finalist in his past two ATP events.
The top 32 seeds receive a bye to the second round, with the leading players making their first appearance over the weekend.
Serbian Novak Djokovic is the second seed, while Stanislas Wawrinka, the Australian Open champion from Switzerland, is third seed for the season's first ATP World Tour Masters 1000 tournament.
On the women's side, the second round starts on Friday and among those in action will be second seed Agnieszka Radwanska of Poland, who hits the court against qualifier Heather Watson of Great Britain.
Third seed Victoria Azarenka of Belarus will start her campaign against American Lauren Davis.
Former world number one Caroline Wozniacki, who lost last year's final to Maria Sharapova, will play Serbia's Bojana Jovanovski.
Australian Open champion Li Na is the top women's seed and meets compatriot Jie Zheng in the second round. Zheng outlasted Paula Ormaechea of Argentina 3-6 6-3 7-6(5) on Thursday.
BNP Paribas Open men's results
Ivo Karlovic (Croatia) beat Alex Bogomolov Jr (Russia) 6-4 6-4
Ryan Harrison (U.S.) beat Andrey Golubev (Kazakhstan) 6-4 7-5
Paul-Henri Mathieu (France) beat Robby Ginepri (U.S.) 6-2 6-3
Jeremy Chardy (France) beat Rhyne Williams (U.S.) 7-6(5) 7-5
Lleyton Hewitt (Australia) beat Matthew Ebden (Australia) 7-6(2) 3-6 6-3
Juan Monaco (Argentina) beat Peter Polansky (Canada) 6-4 6-7(5) 6-4
Santiago Giraldo (Colombia) beat Daniel Gimeno-Traver (Spain) 6-3 4-6 6-4
Lukas Rosol (Czech Republic) beat Dusan Lajovic (Serbia) 6-7(2) 7-5 6-4
Jiri Vesely (Czech Republic) beat Igor Sijsling (Netherlands) 3-6 6-4 7-6(1)
Radek Stepanek (Czech Republic) beat Denis Istomin (Uzbekistan) 6-1 3-6 6-1
Michael Russell (U.S.) beat Donald Young (U.S.) 4-6 6-1 6-2
Tim Smyczek (U.S.) beat Jack Sock (U.S.) 6-4 1-6 6-4
Sergiy Stakhovsky (Ukraine) beat Lukasz Kubot (Poland) 6-4 7-5
Edouard Roger-Vasselin (France) beat Benjamin Becker (Germany) 6-4 6-2
Alejandro Falla (Colombia) beat Federico Delbonis (Argentina) 6-3 6-4
BNP Paribas Open women's results
Coco Vandeweghe (U.S.) beat Alexandra Cadantu (Romania) 6-4 6-0
Elina Svitolina (Ukraine) beat Monica Puig (Puerto Rico) 6-4 7-5
Monica Niculescu (Romania) beat Marina Erakovic (New Zealand) 6-2 6-2
Donna Vekic (Croatia) beat Olivia Rogowska (Australia) 6-0 7-5
Maria Teresa Torro (Spain) beat Galina Voskoboeva (Kazakhstan) 6-1 1-0 (Voskoboeva retired)
Francesca Schiavone (Italy) beat Mona Barthel (Germany) 3-6 6-2 6-2
Camila Giorgi (Italy) beat Andrea Petkovic (Germany) 6-7(5) 6-3 6-3
Alisa Kleybanova (Russia) beat Victoria Duval (U.S.) 5-7 6-4 6-4
Ajla Tomljanovic (Croatia) beat Lourdes Dominguez Lino (Spain) 6-4 7-6(2)
Zheng Jie (China) beat Paula Ormaechea (Argentina) 3-6 6-3 7-6(5)
Julia Goerges (Germany) beat Jana Cepelova (Slovakia) 6-1 2-6 6-3
Karolina Pliskova (Czech Republic) beat Michelle Larcher de Brito (Portugal) 6-2 3-6 6-2
Taylor Townsend (U.S.) beat Karin Knapp (Italy) 7-6(1) 6-1
Aleksandra Wozniak (Canada) beat Urszula Radwanska (Poland) 6-2 6-0
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