A promising approach to combat SARS-CoV-2 constitute small interfering (si)RNAs. We systematically analyzed which SARS-CoV-2 replication steps are accessible for RNAi. We found that siRNAs can target the genome of incoming SARS-CoV-2 terminating replication after cell entry and preventing cytopathy. Suprisingly, siRNAs were not active against intermediate negative sense transcripts. Targeting sequences shared by different viral transcripts allowed simultaneous suppression of genomic and subgenomic viral RNAs by a single siRNA. The most effective suppression of viral replication and spread was achieved by siRNAs targeting open reading frame 1 (ORF1) which is solely part of genomic RNA. We propose that an improved accessibility of translational-active ORF1 during early replication, as well as the outcompetition of RNAi factors by common sequences of transcripts are responsible for this. Our work encourages efforts to develop siRNA-based therapies for COVID-19. Targeting ORF1, together with early treatment start or prophylactic use may be key for high antiviral efficiency.