Gestational diabetes mellitus (GDM) is a common pregnant disorder that needs careful medical attention. N‐acetyl‐L‐cysteine (NAC) is a well‐recognized antioxidant to treat oxidative stress‐induced diseases. Although its role in GDM has been reported, the mechanism remains largely unknown. Therefore, our current study further explored its protective role against GDM. An 8‐week‐old, db/+, female mice were injected with a single dose of 100 mg/kg streptozotocin (STZ) to induce diabetes. Pregnant mice were randomly treated with 1200 mg/kg NAC or water daily. On gestational day 19, oral glucose tolerance test was performed, and visceral fat tissue and blood samples were collected. After delivery, litter size and weight were recorded. NAC could effectively improve GDM‐induced glucose intolerance, hyperlipidemia, activated inflammation, and oxidative stress in GDM mice. Moreover, NAC reduced the litter size and weight of GDM mice. NAC also activated the nuclear factor‐erythroid factor 2‐related factor 2 (Nrf2)/heme oxygenase‐1 (HO‐1) signaling pathway in the liver of GDM mice. NAC effectively ameliorated GDM symptoms and the reproductive outcome of GDM mice through inhibiting oxidative stress, inflammation, and hyperlipidemia. Therefore, NAC might serve as a potential candidate drug against GDM.