The search for better tools for interpreting and understanding wastewater surveillance has continued since the beginning of the coronavirus disease 2019 (COVID-19) pandemic. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to mutate, thus complicating the interpretation of surveillance results. We assessed the Omicron variants (BA.1, BA.2, and BA.5) associated with wastewater-derived SARS-CoV-2 RNA trends by estimating the effective reproduction number (Reff) using an epidemic model that integrates explicitly the SARS-CoV-2 N2 gene concentration detected in wastewater through rt-qPCR quantitative analysis. The model inferred COVID-19 cases based on wastewater data and compared them with the ones reported by clinical surveillance. The variant of the SARS-CoV-2 associated with the wastewater-derived viral RNA was monitored through wastewater whole-genome sequencing. Three major waves between January and September 2022 were associated with the Omicron subvariants (BA.1, BA.2, and BA.5). This work showed that disease trends can be monitored using estimates of the effective reproduction number which is simple and easy to understand.