To reduce the energy consumption of ventilation and air-conditioning duct systems, high-efficiency air filtration systems with a smaller pressure drop must be developed. In this work, we conducted a pioneering evaluation of the flow resistance and ultrafine particle (UFP) deposition performance of an air duct fitted with V-shaped winglet vortex generators (VGs). Three pitch ratios (PRs; 2.0, 2.4, and 3.0) and three blockage ratios (BRs; 0.2, 0.4, and 0.6) at an attack angle of 30° were studied in duct airflows. UFPs of 5–100 nm were tested in laminar and turbulent flows with different air velocities ranging from 0.5 m/s to 10 m/s. Friction factors and particle deposition velocities were calculated for empty ducts and ducts with VGs under identical fanning power. In addition, new expressions of the overall particle deposition/hydraulic performance indexes were introduced for laminar and turbulent flows. The experimental deposition velocities of UFPs increased with BR and decreased with PR. The maximum particle deposition enhancement in the ducts with VGs was 11.4 times that in the empty ducts, achieved at PR = 0.2 and BR = 0.6. The ratios of the friction factor of VG-equipped ducts to empty ducts were 1.57–3.84 for laminar flows and 1.25–1.99 for turbulent flows. The particle deposition/hydraulic performance index varied from 1.5 to 9.3 and peaked at PR = 2.0, BR = 0.6, and Reynolds number = 520. The results indicate that V-shaped winglets can be potentially used for developing high-performance and energy-efficient air cleaning devices.