Objectives: a) To analyze the long-term seismicity and understand the potential of seismic quiescence study to use it as a reliable seismic precursor b) To estimate B value and understand the variation in B value as earthquake precursor in seismically active region. Methods: The present study analyses the seismicity pattern from the Andaman- Sumatra region for a period of 1964 to 2018. The area has been divided into epicentral blocks. Earthquakes preceding and succeeding a major earthquake with different seismic phases of quiescence and pattern of seismicity have been studied carefully. All quiescence periods are characterized by high b values and period of major shocks has a low b value. Main shock events for each epicentral block with different phases of quiescence (Q1, Q2 and Q3) and active seismicity have been identified and analyzed. Findings: The study suggests that there is generally approximately 6-12 years of gap between major earthquakes. There are 28 years of quiescence before the major earthquake of the stature of Dec 26, 2004 mega earthquake, suggesting that long term quiescence leads to great earthquakes. The study also proposes that the area between 20 and 60N latitudes shows a long-term quiescence which may lead to a major earthquake in the near future. A thorough analysis of long-term seismicity and seismic quiescence can be used as an earthquake precursor, though with limitations. The latest post seismic quiescence period Q2 after the greater events of 2004 and 2005, may yield an impending event of 6.5 M or even greater. Novelty: The present study deals with the precursor studies of one of the most important tectonic zone. Extensive analysis of 54 Years of data has been done and the scope of using seismicity and b value for the long-term prediction of earthquakes has been examined. The periodicity of seismicity has been used to quantify the precursors. Though various statistical studies have been attempted for this zone, methodology adopted here proved one of the reliable methods to check for the possible mega earthquakes of this seismically active zone, which can be applied to other seismically active areas as well. Keywords: Seismicity; Andaman-Sumatra; Seismic quiescence; B-value; Precursors