Health-related quality of life (HRQoL) is particularly important for women during the postnatal period. This study examined the quality of life and its determinants among lactating mothers in the South-East Senatorial District of Rivers State, Nigeria, using a cross-sectional research design. The study population comprised 1,965 lactating mothers attending postnatal clinics, from which a sample of 983 respondents was selected through a multistage sampling procedure. Data were collected using a structured questionnaire titled Health Survey Instrument and Health-Related Quality of Life Instrument (HSIHRQoL–SF-12v2) and analyzed with the Statistical Package for the Social Sciences (SPSS version 27) using descriptive statistics, multivariate regression, and one-way analysis of variance (ANOVA) at a 0.05 level of significance. The findings revealed that 78.8% of the respondents had a good quality of life, while 21.2% reported a poor quality of life. A very strong positive relationship was observed between income level and quality of life (r = 0.81), with income accounting for 72.6% of the variance in quality of life (R² = 0.726). Statistically significant relationships were also found between quality of life and income level, access to healthcare services, family support, parity, age, and religion (p < 0.05). The study concluded that lactating mothers in the South-East Senatorial District of Rivers State generally had a good quality of life, which is encouraging and should be sustained, and recommended that postnatal clinics adopt a holistic approach by addressing the physical, psychological, and social health needs of both mothers and infants through the availability of qualified healthcare professionals.