Background Ivermectin-based preventive chemotherapy (PC) is distributed annually to all at-risk populations eligible for ivermectin treatment to control and/or eliminate onchocerciasis. Information on the impact of mass ivermectin administration on onchocerciasis transmission is scanty, and it is tricky to appreciate the progress towards elimination and engage corrective measures. To fill that gap in the Centre Region in Cameroon, the current onchocerciasis endemicity level in the Ndikinimeki Health District after about two decades of mass treatments was assessed. Methods A cluster-based cross-sectional survey was carried out in the Ndikinimeki Health District and all volunteers aged ≥ 5 years were (i) interviewed on their compliance to ivermectin over the past five years and (ii) underwent clinical (nodule palpation and visual search for onchocercal lesions) and parasitological examinations (skin snip) for onchocerciasis. Results The overall Onchocerca volvulus prevalence was 7.0% (95% CI: 5.2–9.3%). The prevalence of the disease was significantly higher in the communities Kiboum 1 and Kiboum 2 compared to the other communities (highest prevalence in Makénéné Town Water: 8.5%; 95% CI: 2.3–20.4%) (χ2 = 51.314, df = 11, P = 0.0001). The proportion of systematic non-compliers to ivermectin was 23.3% (95% CI: 19.9–27.1%) among individuals interviewed. In the sentinel sites (Kiboum communities), onchocerciasis prevalence decreased from 95.2% (95% CI: 88.3–98.1%) to 23.7% (95% CI: 14.7–36.0%). Conclusions This study has revealed that the Ndikinimeki Health District is hypo-endemic for onchocerciasis after about two decades of preventive chemotherapy. However, transmission is ongoing, with potential hotspots in the Kiboum 1 and Kiboum 2 communities, which are known as first-line communities (closest to the breeding sites of the vector). Alternative or complementary strategies to annual ivermectin appear compulsory to accelerate the momentum towards onchocerciasis elimination.