Cotton mealybug Phenacoccus solenopsis Tinsley (Homoptera: Pseudococcidae) has caused huge crop and economic losses in different countries of the world including Pakistan. Considering P. solenopsis as a key cotton pest, research was conducted to understand genetics, realized heritability and preliminary mechanism of indoxacarb resistance. As a result of selection with indoxacarb, P. solenopsis developed a 2223.13-fold resistance after five generations. Indoxacarb resistance was autosomal in nature, and the degree of dominance for F1 and F1′ was 0.60 and 0.62, respectively, indicating the incomplete dominance of indoxacarb resistance. A monogenic model of inheritance also showed the involvement of multiple loci in indoxacarb resistance in P. solenopsis. Realized heritability for indoxacarb resistance was markedly high (h2 = 1.13) in P. solenopsis suggesting how quickly resistance can develop as a result of selection. Synergism tests with piperonylbutoxide (PBO) and S,S,S-tributylphosphorotrithioate (DEF) also suggested that indoxacarb resistance in P. solenopsis was metabolism-based due to possible involvement of both mono-oxygenases and esterases. Hence, it was concluded that indoxacarb resistance in P. solenopsis was autosomal, incompletely dominant, polygenic and metabolism-based. These findings will be helpful in the management of P. solenopsis.