Background <p>Colorectal cancer (CRC) significantly impacts health-related quality of life (HRQoL) and sexual function (SF) in patients, with these effects potentially varying by gender. Despite the growing prevalence of CRC in Iran, the gender-specific relationship between HRQoL and SF remains underexplored. This study aims to investigate the association between HRQoL and SF in CRC patients in Iran.</p> Methods <p>A descriptive-correlational study was conducted among 256 CRC patients recruited from oncology centers in Iran through convenience sampling. Participants were assessed using validated and reliable instruments, including a researcher-developed demographic questionnaire, the Short Form-36 (SF-36) for HRQoL, the Female Sexual Function Index (FSFI) for women, and the International Index of Erectile Function (IIEF) for men. The normality of the data was evaluated using kurtosis and skewness indices. Pearson’s correlation coefficients and partial correlation analyses were employed to examine the associations between HRQoL and SF, adjusting for potential confounders. Data were collected and subsequently coded using Stata software (version 17, StataCorp, College Station, TX).</p> Results <p>In this study, 256 colorectal cancer patients (50.4% male, 49.6% female) were analyzed, with a mean age of 50.2 ± 20.4&#xa0;years. Significant associations between HRQoL and sexual function were primarily observed in female patients. In women, strong positive correlations were found between the physical functioning domain of HRQoL and both sexual satisfaction (<i>r</i> = 0.78, <i>p</i> &lt; 0.001) and sexual pain (<i>r</i> = 0.87, <i>p</i> &lt; 0.001). Additional significant correlations included HRQoL physical functioning and sexual desire (<i>r</i> = 0.53), mental stimulation (<i>r</i> = 0.53), lubrication (<i>r</i> = 0.59), orgasm (<i>r</i> = 0.59), and the total FSFI score (<i>r</i> = 0.69) (all <i>p</i> &lt; 0.001). In contrast, no comparable correlations were found in male patients. Energy levels were positively correlated with sexual function in females but negatively in males (e.g., energy/fatigue and sexual satisfaction, <i>r</i> =  − 0.67, <i>p</i> &lt; 0.001), further underscoring gender-specific differences. Social functioning was positively associated with sexual pain (<i>r</i> = 0.54, <i>p</i> &lt; 0.001) and other FSFI domains in women. General HRQoL was also positively correlated with sexual function in women (e.g., total HRQoL and sexual satisfaction, <i>r</i> = 0.56, <i>p</i> &lt; 0.001) but not in men. These findings highlight a clear gender disparity in the interplay between HRQoL and sexual function.</p> Conclusion <p>In conclusion, this study identifies complex, gender-specific associations between HRQoL and sexual function in colorectal cancer patients. Among female patients, better physical functioning and higher energy levels were associated with greater sexual satisfaction, whereas these associations were not observed in male patients, suggesting potential gender differences in sexual health outcomes. In both genders, higher social functioning was positively associated with sexual health, underscoring the possible role of social support. These findings highlight the relevance of considering gender-specific factors when addressing quality of life and sexual health in this population; however, due to the cross-sectional design, causal relationships cannot be inferred. Future research employing longitudinal designs is warranted to better understand the directionality and potential causal pathways of these associations.</p>