Lewandowski shared managerial duties with Sami Hyypia last season, before returning to work with the club's youth side for the current campaign.
Hyypia was sacked earlier this month though, as Leverkusen's miserable form showed no signs of ending, leading to Lewandowski's promotion to the top job.
And Leverkusen, who had won just one of their last 12 matches in all competitions, recorded a timely win that lifted them to fourth, which brings with it the final UEFA Champions League spot.
The new man in charge witnessed his side make a flying start, with Stefan Kiessling's 15th league goal of the season giving the hosts the lead inside the first minute.
Teenager Julian Brandt then scored his second goal in as many matches, with the 17-year-old's clever chip in the 24th minute doubling his side's lead.
Hertha threatened a comeback as Sandro Wagner halved the deficit before the break, but Leverkusen held firm for a desperately needed three points, while the losers have now gone eight league games without a win.
In Sunday's other Bundesliga encounter, Hoffenheim extended their unbeaten run to five with a 2-0 home win over Augsburg.
Just one place separates the two teams in the table, but it was Hoffenheim who opened the scoring in the 19th minute thanks to Sejad Salihovic's stunning free-kick.
And Jannik Vestergaard's effort four minutes before the break was enough to give Hoffenheim a comfortable two-goal win.
