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Uterine fibroids are the most common benign tumors of the female reproductive tract and are frequently associated with heavy menstrual bleeding, inflammation, and hormonal dysregulation. These features predispose affected women to iron deficiency and related hematological alterations. However, data integrating inflammatory markers, iron indices, and progesterone levels in women with uterine fibroid in South-Eastern Nigeria remain limited. This study evaluated erythrocyte sedimentation rate (ESR), serum iron, total iron-binding capacity (TIBC), transferrin saturation, and serum progesterone levels in women diagnosed with uterine fibroid in Imo State, Nigeria. This analytical cross-sectional study included 30 women with ultrasound-confirmed uterine fibroid and 30 age-matched apparently healthy controls. ESR was determined using the Westergren method, serum iron and TIBC were measured colorimetrically, transferrin saturation was calculated, and serum progesterone was assayed using ELISA. Data were analyzed using independent sample t-tests, one-way ANOVA, correlation analysis, and effect size estimation. Statistical significance was set at p < 0.05. Women with uterine fibroid had significantly higher ESR compared with controls (70.37 ±36.53 vs 10.93 ±9.52 mm/hr; p < 0.0001). Serum iron levels were significantly reduced in the fibroid group (12.05 ±4.14 vs 27.78 ±9.53 µmol/L; p < 0.0001), while TIBC was significantly elevated (153.33 ±77.51 vs 71.54 ±26.03 µmol/L; p < 0.0001). Mean transferrin saturation was markedly lower among women with fibroid (10.08%) compared with controls (45.23%), with 86.7% of fibroid patients exhibiting transferrin saturation <20%. Serum progesterone levels were significantly higher in the fibroid group (31.44 ±20.47 vs 6.18 ±7.15 ng/mL; p < 0.0001). Effect size analysis demonstrated very large differences for ESR (Cohen’s d = 2.23) and serum iron (d = −2.14). Age-stratified analysis showed no significant differences across age groups for ESR, iron indices, or progesterone (p > 0.05). Women with uterine fibroid in Imo State exhibit significant inflammatory activity, profound iron deficiency, and elevated progesterone levels compared with healthy controls. The high prevalence of reduced transferrin saturation highlights the clinical importance of routine iron status assessment in fibroid management. These findings underscore the need for integrated inflammatory, hematological, and hormonal evaluation in women with uterine fibroid, particularly in resource-limited settings.