Background: Hyperemesis gravidarum is one of the problems encountered among pregnant women due to persistent and excessive vomiting starting before the end of the 22nd week of gestation. The current study aimed to assess the prevalence of hyperemesis gravidarum and associated factors among pregnant women at comprehensive specialized hospitals in northwest Ethiopia. Methods: A multi-facility-based cross-sectional study was conducted at comprehensive specialized hospitals from 1st June 2022 to 30th July 2022. The data were entered using EPI Data Version 4.6 statistical software and analyzed using SPSS Version 26. Descriptive statistics such as frequency, mean, and percentage were calculated. Univariable and multivariable binary logistic regression analyses were carried out to identify the associated factors of hyperemesis gravidarum. Results: In all, 404 study participants were enrolled. About 16.8% of pregnant women were found to have hyperemesis gravidarum. Age < 20 year (AOR = 3.170; 95% CI: 1.119, 8.980), study participants who cannot read and write (AOR = 5.662; 95% CI: 2.036, 15.7470), grade 1–8 (AOR = 4.679; 95% CI: 1.778, 12.316), and grade 9–10 (AOR = 8.594; 95% CI: 3.017, 24.481), being housewife (AOR = 6.275; 95% CI: 1.052, 37.442), living in urban area (AOR = 2.185; 95% CI: 1.035, 4.609), having previous hyperemesis gravidarum (AOR = 2.463; 95% CI: 1.210, 5.012), having family history of hyperemesis gravidarum (AOR = 2.014; 95% CI: 1.002, 4.047), unplanned pregnancy (AOR = 2.934; 95% CI: 1.030, 8.351), having recent abortion (AOR = 2.750; 95% CI: 1.010, 7.483), and gravidity (AOR = 1.956; 95%CI: 1.023, 3.737) were factors associated with hyperemesis gravidarum. Conclusion: The prevalence of hyperemesis gravidarum is higher. Low maternal age, lower educational level, being a housewife, being an urban resident, having previous hyperemesis gravidarum, having a family history, having an unplanned pregnancy, and having a recent abortion were significantly associated with hyperemesis gravidarum.