Objectives <p>This study aimed to determine the effectiveness of a mindfulness-based program on stress, salivary cortisol levels, marital relationships, and the incidence of successful pregnancy in infertile couples undergoing Assisted Reproductive Treatment.</p> Method <p>A randomized-controlled trial parallel design with two groups and repeated measures. Seventy-five infertile couples were randomly assigned into the control group (<i>n</i> = 37) and the experimental group (<i>n</i> = 38) receiving a mindfulness-based program. Repeated measures multivariate analysis of variance (MANOVA), independent <i>t</i>-test, and chi-square test were used in data analysis.</p> Results <p>Stress and marital relationships of infertile women and their spouses in the experimental and control groups were statistically significant differences over time (<i>p</i> &lt; 0.001, <i>η</i>^<i>2</i> = 0.76; <i>p</i> &lt; 0.001, <i>η</i>^<i>2</i> = 0.75, respectively). At time 4, the infertile women and their spouses in the experimental group showed statistically significant differences in at least one pair in stress (<i>p</i> &lt; 0.001, <i>η</i>^<i>2</i> = 0.87; <i>p</i> &lt; 0.001, <i>η</i>^<i>2</i> = 0.85, respectively) and marital relationships (<i>p</i> &lt; 0.001, <i>η</i>^<i>2</i> = 0.85; <i>p</i> &lt; 0.001, <i>η</i>^<i>2</i> = 0.80, respectively). The salivary cortisol levels in the infertile women were statistically significant differences (<i>p</i> &lt; 0.05). Finally, the rates of successful pregnancy in the infertile women were also statistically significant differences (<i>p</i> &lt; 0.05).</p> Conclusions <p>The mindfulness-based program can reduce stress and enhance marital relationship in infertile couples. This program can enhance successful pregnancy in infertile couple.</p> Preregistration <p>Thai Clinical Trials Registry, TCTR ID: TCTR 20221014004.</p>