Several studies have implicated codeine use in the aetiopathogenesis of male infertility. The purpose of this study was to investigate the role of HER2, Ki67, oestrogen and p53/Bcl-2 signaling pathways and the possible outcome of codeine cessation on codeine-induced reproductive toxicity. Thirty adult male Wistar rats of comparable ages and weights were randomly allocated into 5 groups. The control animals received distilled water , while animals in the low-dose (LDC) and high dose (HDC) codeine-treated groups received 2 and 5 mg/kg/day of codeine respectively for 6 weeks. The animals in the low-dose codeine recovery (LDC-R) and high-dose codeine recovery (HDC-R) groups received treatment as LDC and HDC respectively followed by another drug-free six weeks, recovery period. Cessation of codeine exposure led to a partial reversal of codeine-induced poor sperm quality, reduced litter size and weight, increased oxidative testicular injury, testicular apoptosis, and testicular DNA damage caused by codeine administration. Codeine-induced gonado-spermotoxicity was associated with a reduction of circulatory testosterone, suppression of testicular HER2, Ki67, and Bcl-2 expression, down-regulation of oestrogen signaling, and upregulation of testicular caspase 3 activities and p53 signaling pathway. Conclusion: Upregulation of oestrogen signaling associated with enhanced testicular HER2 and Ki67 expression during the recovery period is seemingly beneficial in protecting against codeine-related testicular injury and infertility.