<p>Although knowledge of the factors associated with quality of life in women after childbirth are essential for optimizing maternity care, there is scarcity of evidence on quality of life of postpartum women in Ethiopia. To identify the causal mechanisms of direct and indirect factors associated with health-related quality of life in postpartum women health facility linked community-based longitudinal cohort study was done with 775 mothers in Northwest Ethiopia from October 2020–March 2021. Health-related quality of life was measured by the Amharic version of the shortened World Health Organization Quality of Life (WHOQOL-BREF) instrument. A structural equation statistical analysis method was used to determine the direct and indirect effects of predictor variables on individual domains of Health-Related Quality of Life (HRQOL) as measured by the WHOQOL-BREF-26 items. Fear of childbirth (β = − 0.18 to − 0.06) had a direct negative effect on s environmental quality of life at the first, second and third follow up period. Anxiety (β = − 0.92 to − 0.31) had also a direct negative effect on the four domains of HRQOL throughout the follow up period. Similarly, higher functional disability score (β = − 0.36 to − 0.15) as measured by the World Health Organization Disability Assessment Schedule (WHODAS) had a direct negative effect on the four domains of HRQOL throughout the follow up period. Whereas, higher social support scale (β = 0.97 to 1.64) had a direct positive effect on the four domains of HRQOL at the three follow up periods. Indirect maternal morbidity (β = -3.37) had a direct negative effect on the physical quality of life at the third follow up period. Anxiety (β = -0.34 to -0.18) had also an indirect negative effect through WHODAS total score on the physical, psychological and environmental quality of life throughout the follow up period and on the social quality of life at the first and second follow up period. In addition, fear of child birth (β = -0.06 to -0.03) had also an indirect negative effect through WHODAS total score on the four domains of HRQOL throughout the follow up period. Similarly, social support (β = 1.09 to 1.53) had an indirect positive effect through fear of birth and WHODAS total score on the four domains of quality of life throughout the follow up period. In the postpartum period, anxiety screening and therapy may help to improve maternal health-related quality of life. Supplying sufficient details regarding birthing processes, responding to women’s needs during giving birth, and intervention strategies for negative appraisals of childbirth are essential to avert quality of life impairment in postpartum women.</p>