Female infertility is a widespread concern affecting millions globally, with a significant portion concentrated in India alone, comprising approximately 25% of the affected population. Despite advancements in assisted reproductive technologies (ART) offering solutions to certain infertility challenges, the underlying molecular mechanisms contributing to fertility impairments remain complex and often poorly understood. Female fertility is a complex process influenced by various genetic and environmental factors. Sirtuins and Nrf2 genes have emerged as key players in maintaining reproductive health, particularly in the context of comorbid conditions such as obesity, hypothyroidism, diabetes, and polycystic ovary syndrome (PCOS). Sirtuins, a family of NAD+-dependent class 3 histone deacetylases (HDACs), were initially identified as longevity genes. However, subsequent studies have revealed their involvement in various physiological processes, including cell proliferation, apoptosis, cell cycle progression, and insulin signaling, which are crucial for female fertility. Sirtuins have been shown to activate the Nrf2 pathway, a transcription factor involved in the antioxidant response and cellular defense against oxidative stress. The interplay between these two genes has been implicated in modulating female fertility outcomes. This review aims to summarize the current understanding of the role of sirtuins and Nrf2 genes in female fertility, focusing on their individual and combined effects in the presence of comorbid conditions. We will discuss the molecular mechanisms by which these genes influence reproductive health, including the regulation of oocyte quality, embryo development, implantation, and endometrial receptivity, this review aims to provide a comprehensive understanding of their role in female fertility outcomes.