Flonicamid is a chordotonal modulator and novel systemic insecticide that has been used frequently for controlling a broad range of insect pests.The risk of flonicamid resistance was assessed through laboratory selection and determining inheritance pattern and cross-resistance potential to five insecticides in house fly, Musca domestica L. Very low to high flonicamid resistance in M. domestica populations was found compared with the susceptible strain (SS). A flonicamid-selected (Flonica-RS) M. domestica strain developed 57.73-fold resistance to flonicamid screened for 20 generations compared with the SS. Overlapping 95% fiducial limits of LC₅₀ of the F₁ and F₁ ^ǂ, and dominance values (0.87 for F₁ and 0.92 for F₁ ^ǂ) revealed an autosomal and incomplete dominant flonicamid resistance.The monogenic model of resistance inheritance suggested a polygenic flonicamid resistance.The Flonica-RS strain displayed negative cross-resistance between flonicamid and sulfoxaflor (0.10-fold) or clothianidin (0.50-fold), and very low cross-resistance between flonicamid and flubendiamide (4.71-fold), spinetoram (4.68-fold), or thiamethoxam (2.02-fold) in comparison with the field population. The estimated realized heritability (h²) value of flonicamid resistance was 0.02. With selection mortality 40–90%, the generations required for a 10-fold increase in LC₅₀ of flonicamid were 94–258 at h² (0.02) and slope (3.29). Flonicamid resistance was inherited as autosomal, incomplete dominant, and polygenic in the Flonica-RS. Negative or very low cross-resistance between flonicamid and sulfoxaflor, clothianidin, flubendiamide, spinetoram, and thiamethoxam means that these insecticides can be used as alternatives for controlling M. domestica.These data can be useful in devising the management for M. domestica.