Background: Sensory integration dysfunction (SID) often involves sensory modulation difficulties that can significantly impair daily functioning and health-related quality of life (HRQoL) in adults. Despite its prevalence, the relationship between sensory modulation profiles and HRQoL in adults with SID remains underexplored. Understanding this link is essential for developing targeted interventions to address diverse symptom profiles. Objectives: This study examined the association between sensory modulation difficulties and multiple HRQoL dimensions in adults with SID. Methods: A cross-sectional quantitative study included 86 adults aged 23–54 years, divided into two groups: adults with SID and healthy controls. Sensory modulation was assessed using the Adolescent/Adult Sensory Profile Questionnaire, and HRQoL was measured with the SF-36 instrument. Statistical analyses included the Kolmogorov-Smirnov test, Mann-Whitney U test, and Pearson’s correlation. The null hypothesis tested for no differences in HRQoL scores between groups. Results: Significant differences were found between groups across all eight SF-36 domains and the overall HRQoL score (p < 0.001), with controls consistently scoring higher in each domain. Correlation analyses showed no significant associations between HRQoL outcomes and demographic variables (age, gender). Conclusion: These findings confirm a strong association between SID and reduced HRQoL in adults, affecting both physical and mental health. The consistent impact across age and gender groups highlights the importance of personalized therapeutic approaches.