(1) Background: A proper assessment of disease activity is crucial for the management of a patient with rheumatoid arthritis (RA). Platelets seem to be involved in joint inflammation pathophysiology. Platelet indices (PIs) are markers of platelet activation, and include platelet count (PC), mean platelet volume (MPV), platelet distribution width (PDW) and plateletcrit (PCT). The purpose of the study was to assess the relationship between PIs and disease activity markers, both systemic (clinical, laboratory) and local (ultrasound, US), in patients with RA; (2) Methods: The study group consisted of 131 consecutive RA patients. The following assessments were performed: joint counts, Disease Activity Score (DAS28), complete blood cell counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and US of 24 small joints; (3) Results: Mean values of PIs remained within the normal reference ranges. Values of PC, PCT, PDW were significantly associated with disease activity markers, both clinical (DAS28, joint counts) and laboratory (CRP, ESR). In patients with high disease activity, PC, PCT were significantly higher and PDW lower. PC was positively correlated with Power Doppler US (PDUS) score. In patients with features of RA severity (antibodies positivity, extra-articular manifestations) PC and PCT were positively associated with all US parameters (Grey Scale US, PDUS, Global scores); (4) Conclusions: In patients with RA, PC and PCT may serve as positive disease activity markers and PDW may serve as a negative marker. PIs may be used as reliable, inexpensive markers of RA systemic activity; they may also serve as markers of local inflammation in the joints affected by RA.