The veteran Australian took one hour and 39 minutes to defeat the Spanish sixth seed 7-5 6-3, setting up a quarter-final clash with Romanian qualifier Marius Copil.
After a sluggish start, where Hewitt was broken in the third game of the opening set and then saved several break points against him, the world No.60 levelled the set at 5-all when Lopez double-faulted to give the Australian a break.
Hewitt sealed his subsequent service game with a clever shot which had him roaring at the crowd with clenched fists before back-to-back double-faults by Lopez gave him the opening set 7-5.
A fired-up Hewitt secured the crucial break in the sixth game of the second set, going on to wrap up the win with an ace.
It's the first time since 2009 Hewitt has won back-to-back matches in his opening ATP Tour event of the year and keeps him on track for a dream final match-up with 17-time grand slam champion Roger Federer.
Copil's upset win over third-seeded Frenchman Gilles Simon has opened up Hewitt's side of the draw, with the world No.147 defeating the former Australian Open quarter-finalist 7-5 6-3 in their first clash.
Earlier, eighth-seeded Frenchman Jeremy Chardy beat compatriot Nicolas Mahut 7-5 6-7 (7-4) 6-3 to move into the quarter-finals.
World No.34 Chardy, 26, will play the winner of Australian Sam Groth's second-round clash with South African fourth seed Kevin Anderson to be played on Thursday night.
Mahut had made more of a name for himself in Brisbane as Federer's doubles partner at the tournament but kept former Wimbledon junior champion Chardy honest by clinching the second set.
But world No.50 Mahut, 31, could not sustain the pressure and buckled as Chardy emerged triumphant.