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Abstract Introduction Pregnant women may need to undergo non‐obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane‐induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO‐induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO. Methods Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00–18:00 h) during GD15–21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti‐inflammatory markers and synaptic function‐related proteins were assessed using molecular biology methods. Results The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐alpha and a reduction in the hippocampal levels of IL‐10, synaptophysin, post‐synaptic density‐95, growth‐associated protein‐43, and brain‐derived neurotrophic factor. Conclusion Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.