Background Hypertension is common and leads to negative outcomes. Intensive blood pressure (BP) lowering can reduce cardiovascular events and all‐cause mortality, but its benefits for patients with hypertension with multiple comorbidities are uncertain. This study aimed to explore how comorbidities affect the clinical outcomes of intensive BP lowering in participants from the SPRINT (Systolic Blood Pressure Intervention Trial). Methods We analyzed data from the SPRINT data set and calculated each patient's comorbidity score using the Charlson Comorbidity Index (CCI). The primary end point was major adverse cardiovascular and cerebrovascular events, including cardiovascular death, heart failure, myocardial infarction, acute coronary syndrome not leading to myocardial infarction, and stroke. Secondary end points included each component of the primary end point and all‐cause death. Results We categorized 9361 patients into 3 groups based on CCI scores: 0, 1 to 2, and ≥3. Patients with higher CCI scores had more cardiovascular and cerebrovascular comorbidities. Intensive BP treatment significantly lowered the risk of major adverse cardiovascular and cerebrovascular events in patients with CCI scores of 0 (7.1% versus 10.9%; adjusted hazard ratio [HR], 0.634 [95% CI, 0.474–0.848]; P=0.002) and 1 to 2 (12. 8% versus 17.2%; adjusted HR, 0.729 [95% CI, 0.588–0.905]; P=0.004), but not in those with CCI ≥3 (23.3% versus 23.5%; adjusted HR, 0.907 [95% CI, 0.683–1.206]; P=0.502). It also reduced the risk of cardiovascular mortality across all CCI groups. Subgroup analyses revealed that intensive BP lowering was beneficial for major adverse cardiovascular and cerebrovascular events in most demographic and clinical subgroups with mild or moderate comorbidities. However, in the severe comorbidity subgroup, its benefits were limited to patients with atrial fibrillation. Certain medications, such as nonselective β‐blockers and diuretics, were associated with higher major adverse cardiovascular and cerebrovascular event risk in patients with mild comorbidities, whereas others showed varying effects based on comorbidity severity. Conclusions Intensive BP control decreased cardiovascular events and mortality in patients with mild or moderate comorbidity burden, particularly in those with mild comorbidities. This emphasizes the importance of optimizing BP management even in patients with hypertension without extensive comorbid conditions, as their risk may be underestimated. Registration URL: clinicaltrials.gov; Unique Identifier: NCT01206062.