<p>Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy affecting women in the reproductive age range, which is thought to be the primary cause of anovulatory infertility. This condition is complex and heterogeneous. The current study is aimed at determining the potential ameliorative effects of bromelain and metformin, either separately or in combination, in the reduction of letrozole-induced PCOS in female rats by focusing on the inflammatory axis, homeostasis model assessment of insulin resistance (HOMA-IR), and silencing information regulator 2-related enzyme 1 (SIRT1). The study was performed on 48 female albino rats divided into 6 groups (control, vehicle, untreated PCOS, PCOS + metformin, PCOS + bromelain, combined), vaginal smear was done to evaluate ovarian cyclicity and biochemical parameters, and the histopathological picture of ovarian tissue was assessed. Administration of either bromelain or metformin revealed significant reduction in ovarian weight (OW) and serum levels (testosterone, luteinizing hormone (LH)) and improvement of vaginal smear and histopathological picture, bromelain revealed more significant reduction of body weight (BW), serum level of follicular stimulating hormone, and tissue level of tumor necrosis factor α (TNFα), while metformin revealed more significant reduction of insulin resistance (IR) by assessment of HOMA-IR and increase tissue level of SIRT1, while the values of BW (<i>p</i> &lt; 0.001), OW (<i>p</i> &lt; 0.01), testosterone (<i>p</i> &lt; 0.05), LH (<i>p</i> &lt; 0.05), fasting glucose (<i>p</i> &lt; 0.01), fasting insulin (<i>p</i> &lt; 0.01), HOMA-IR (<i>p</i> &lt; 0.01), and TNFα (<i>p</i> &lt; 0.001) decreased in bromelain treated group compared to diseased group; the values of FSH/LH ratio (<i>p</i> &lt; 0.05) and SIRT1 (<i>p</i> &lt; 0.05) increased; and these advantageous benefits were markedly more pronounced in rats administered the combined treatment compared to monotherapy.</p>