Cyclaniliprole, a type of the third-generation anthranilic diamide insecticide, was mainly used for management of various pests. Myzus persicae (Hemiptera: Aphididae), known as the peach-potato aphid, is an economically essential pest with worldwide distribution. However, the risk assessment of cyclaniliprole in M. persicae is unclear. The cyclaniliprole risk assessment in M. persicae showed 2.56-fold resistance to cyclaniliprole after 26 generation selection in comparison to the initial susceptible population. The cross-resistance experiment revealed that the low cross-resistance to imidacloprid (4.2-fold) in the cyclaniliprole-selected strain was observed when comparing to the susceptible population. Realized heritability (h2) of cyclaniliprole resistance was 0.0362. When mean slope = 2.217 and h2 = 0.0362, then 31–69 generations would be required for an increase of LC50s with ten times at 90%–50% selection intensity. The fecundity (the number of offspring per female) of the cyclaniliprole-selected strain had no significant difference with the susceptible population. The mRNA expression of the target gene ryanodine receptor was significantly enhanced in the cyclaniliprole-selected strain. The absence of fitness costs, the minimal resistance risk, and very low levels of cross-resistance in the cyclaniliprole-selected strain provide strong support for designing the effective management strategies against M. persicae.