Abstract Introduction: Uterine fibroids can be associated with poor health-related quality of life (HRQoL) when symptomatic. Our objective was to assess the severity of uterine fibroid symptoms (UFSs) and its impact on perceived HRQoL among women with uterine fibroids attending selected secondary and tertiary health institutions across Nigeria. Materials and Methods: This was a prospective and questionnaire-based cross-sectional survey. Data collected included demographics, symptoms severity, medical/gynecological history, mental health status, perceived HRQoL, and myomectomy benefits. The study was conducted between May 1, 2019 and August 31, 2019, across the six geopolitical zones in Nigeria, namely: Northeast, Northwest, North Central, South–South, Southeast, and Southwest zones, including Lagos. A total of 464 women were interviewed. Results: The average age of the respondents was 37 years (range 18–59 years). About 81%–87% experienced UFS-related menstrual disorders, with 50% experiencing moderate to severe symptoms. Overall, up to 70% of the women indicated that UFS impacted their HRQoL, with the majority reporting moderate to severe impact across all domains, including concern (55.6 ± 26.6), control (54.3 ± 26.4), self-conscious (53.5 ± 27.3), energy/mood (52.1 ± 24.5), and sexual function (49.1 ± 26.4). About 75% reported improvements after myomectomy. Conclusion: This study revealed that a significant number of women with uterine fibroids had symptoms affecting their perceived HRQoL. Many of the respondents reported a decreased overall HRQoL with significant improvement after myomectomy. Early recourse to definitive care is therefore imperative in the quest to improve overall HRQoL, including reproductive health.