This study aimed to assess health related quality of life (HRQoL) in adult patients with Crohn’s disease (CD), considering disease severity and gender differences, and also its relationship with nutritional status. Consecutive adult patients aged 18–65 years with CD were recruited. Disease activity was clinically defined by the Crohn’s Disease Activity Index (CDAI) in active and quiescent phases. HRQoL was evaluated using the validated short form (SF)-36 questionnaire for the Italian population. Additionally, anthropometry, bioimpedance analysis, and handgrip-strength (HGS) were performed. Findings showed that 135 patients (79 men and 56 women) were included, having a mean age of 38.8 ± 14 years and a BMI of 23.2 ± 3.7 kg/m2. Overall, active CD patients had a lower perception of their QoL compared to those clinically quiescent, while gender differences emerged mostly in the quiescent group. Interestingly, HRQoL was significantly associated with many nutritional variables, and muscle strength was the main predictor. Therefore, HRQoL is perceived lower in active compared to quiescent patients, but women experienced poorer QoL than men, especially in the quiescent phase. Finally, higher QoL scores were found in subjects being in clinical remission phase with a preserved muscle function. However, further studies are still required to verify these findings.