Jurgen Klopp's side have started the new campaign brilliantly, posting victories in all four of their league fixtures.
New signings Pierre-Emerick Aubameyang and Henrikh Mkhitaryan have slotted in seamlessly, scoring five Bundesliga goals between them, and Klopp's men look a serious threat to reigning champions Bayern Munich this season.
Dortmund's defence has also been in form, conceding just two goals in their four fixtures, and they will head into Saturday's match brimming with confidence.
Lewandowski hurt his knee in a FIFA World Cup qualifier against Montenegro on Friday, and had to pull out of Tuesday's fixture against San Marino as a result.
The striker, who scored 36 goals in all competitions for Dortmund last term, was diagnosed with tendonitis in his left knee by his club's medical staff.
Mkhitaryan may play more of an advanced role if Lewandowski misses out, with the Armenia international scoring twice in Dortmund's last match, a 2-1 win at Eintracht Frankfurt.
Despite conceding an early goal, Hamburg came from behind to win 4-1 as Son Heung-Min, who moved to Bayer Leverkusen in the close-season, and Artjoms Rudnevs scored doubles.
Van der Vaart's absence may give Turkey international Hakan Calhanoglu a chance to shine, though.
The 19-year-old made his international debut on Friday in Turkey's 5-0 World Cup qualifying win over Andorra, while he also scored twice off the bench – after replacing Van der Vaart – in Hamburg's recent 4-0 triumph.
