Background: In clinical practice, distinguishing disease activity in patients with rheumatological illnesses is challenging. Objectives: We aimed to investigate clinical associations of hemogram-derived indices, namely: red cell distribution width (RDW), mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) with disease activity in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS). Methods: In 250 patients with rheumatological disease and 100 healthy age-matched controls, we investigated disease activity scores and indicators and evaluated their association with hemogram-derived indices values. Results: Compared with the control group, RDW, MPV, and PLR significantly increased ( P < .001) in the three studied disorders (RA, SLE, and AS), but LMR dramatically decreased. SII was considerably higher in RA and AS patients compared with controls but not in SLE patients. On the other hand, NLR rose dramatically in SLE patients compared with controls ( P = .043), but did not change much in RA and AS patients ( P > .05). RDW and MPV showed significant changes ( P < .001) in the three studied diseases (RA, SLE, and AS) according to disease activity. They significantly increased across worsening activity scores. Only in the SLE group, PLR was significantly increased with disease activity ( P < .001), while LMR showed a significant decrease ( P = .016). Conclusions: Clinicians must pay close attention to complete blood count (CBC) analysis and its various derived ratios to better characterize the activity of rheumatological disorders and anticipate the disease course and prognosis.