公元前15世纪末叶以后，亚述又开始强大起来，进入中亚述时期，但当时的形势对亚述来说十分不利，小亚细亚的赫梯王国和新王国时期的埃及都在叙利亚扩张自己的势力，从而阻断了亚述向西的扩张。然而亚述仍不断寻找扩张机会，先是打败了两河流域南部的加喜特人，将亚述的边界向南推进，又两度同米坦尼作战，迫使米坦尼与自己的竞争对手埃及结盟，然而亚述最后还是歼灭了米坦尼，占其所有国土。公元前13世纪初，亚述甚至威胁到赫梯的安全，使赫梯也同样向自己的竞争对手埃及结盟。亚述也曾西征腓尼基，自赫梯灭亡后，中亚述王国曾一度统一两河流域。但其后受到阿拉美亚人入侵，令亚述国力受挫。
商业方面，由于赫梯强大，亚述已不能再在小亚细亚建立新的商业殖民地，亚述商人不得不将资本转入国内。然而，亚述本身生产力不是非常发达，回流商业资本无法转入生产过程，于是转成了高利贷资本，侵入农村，导致贫富悬殊日益严重，小生产者丧失土地，甚至遭到债务奴役。在“中期亚述法典”中有反映了这种情况，此法典现存九表，荆三表保存较完整，第一表是有关财产关系的，其中涉及土地转让的条款甚多；第二表则与债务及债务奴役有关，当中记载债务奴役没有年限。在这时留下的私法文书中，也有不少关于土地买卖的契约，反映了商品货币关系深入农村的情况。
政治方面，中亚述时期阶级矛盾尖锐，亚述的王权相对加强，并采用了君主专制的统治方式。在亚舒尔乌里巴特一世统治时期（公元前1365－1330年），第一次在官方名表和印章上自称为“亚述国之王”，并与埃及法老称为兄弟。在阿达德·尼拉里一世时，国王更身兼名年官一职，彻底成为专制君主。
中亚述时期君主
* 伊里巴阿达德一世 前1392年-前1366年
* 亚述路巴里特一世 前1365年-前1330年
* 恩利尔尼拉里 前1330年-前1319年
* 阿里克-登-伊利 前1319年-前1308年
* 阿达德尼拉里一世 前1308年-前1275年
* 萨尔玛那萨尔一世 前1275年-前1245年
* 图库尔蒂-尼努尔塔一世 前1245年-前1208年
* 亚述纳迪纳普利 前1207年-前1204年
* 亚述尼拉里三世 前1203年-前1197年
* 恩利尔-库杜里-乌苏尔 前1197年-前1193年
* 尼努尔塔-阿帕尔-伊库尔 前1192年-前1180年
* 亚述-丹一世 前1179年-前1133年
* 亚述雷什伊希一世 前1133年-前1116年
* 提格拉特帕拉沙尔一世 前1116年-前1077年
* 阿沙里德-阿帕尔-伊库尔 前1077年-前1074年
* 亚述贝尔卡拉 前1074年-前1057年
* 沙姆希阿达德四世 前1057年-前1050年
* 亚述那西尔帕一世 前1050年-前1032年
* 萨尔玛那萨尔二世 前1031年-前1020年
* 亚述尼拉里四世 前1020年-前1016年
* 亚述拉比二世 前1016年-前973年
* 亚述雷什伊希二世 前973年-前967年
* 提格拉特帕拉沙尔二世 前967年-前935年
* 亚述-丹二世 前935年-前912年
(Scholars variously date the beginning of the "Middle Assyrian period" to either the fall of the Old Assyrian kingdom of Shamshi-Adad I, or to the ascension of Ashur-uballit I to the throne of Assyria.)
Ashur-uballit I
In the 15th century BC, Saushtatar, king of Hanilgalbat (Hurrians of Mitanni), sacked Ashur and made Assyria a vassal. Assyria paid tribute to Hanilgalbat until Mitanni power collapsed from Hittite pressure from the north-west and Assyrian pressure from the east, enabling Ashur-uballit I (1365 BC – 1330 BC) to again make Assyria an independent and conquering power at the expense of Babylonia; and a time came when the Kassite king in Babylon was glad to marry the daughter of Ashur-uballit, whose letters to Akhenaten of Egypt form part of the Amarna letters. This marriage led to disastrous results, as the Kassite faction at court murdered the Babylonian king and placed a pretender on the throne. Assur-uballit promptly marched into Babylonia and avenged his son-in-law, making Kurigalzu of the royal line king there.
Assyrian expansion
Hanilgalbat was finally conquered under Adad-nirari I, who described himself as a "Great-King" (Sharru rabû) in letters to the Hittite rulers. The successor of Adad-nirari I, Shalmaneser I (c. 1300 BC), threw off the pretense of Babylonian suzerainty, made Kalhu his capital, and continued expansion to the northwest, mainly at the expense of the Hittites, reaching Carchemish and beyond.
Shalmaneser's son and successor, Tukulti-Ninurta I, deposed Kadashman-Buriash of Babylon and ruled there himself as king for seven years, taking on the old title "King of Sumer and Akkad". Another weak period for Assyria followed when Babylon revolted against Tukulti-Ninurta, and later even made Assyria tributary during the reigns of the Babylonian kings Melishipak II and Marduk-apal-iddin I.
The correct chronology of these Assyrian kings is still is much debated. There are four crucial solar eclipse records. For example, the Assyrian eclipse associated with June 15, 763 BC is widely accepted by the defenders of a middle chronology, but three ignored solar eclipses from the reign of Esarhaddon would affect the calculation drastically.
Tiglath-Pileser I reaches the Mediterranean Sea
As the Hittite empire collapsed from onslaught of the Phrygians (called Mushki in Assyrian annals), Babylon and Assyria began to vie for Amorite regions, formerly under firm Hittite control. When their forces encountered one another in this region, the Assyrian king Ashur-resh-ishi I met and defeated Nebuchadnezzar I of Babylon.
The son of Ashur-resh-ishi's, Tiglath-Pileser I, may be regarded as the founder of the first Assyrian empire. In 1120 BC, he crossed the Euphrates, capturing Carchemish, and defeated the Mushki and the remnants of the Hittites — even claiming to reach the Black Sea. He advanced to the Mediterranean, subjugating Phoenicia, where he hunted wild bulls. He also marched into Babylon twice, assuming the old title "King of Sumer and Akkad", although he was unable to depose the actual king in Babylonia, where the old Kassite dynasty had now succumbed to an Elamite one.
Society in the Middle Assyrian period
Assyria had difficulties with keeping the trade routes open. Unlike the situation in the Old Assyrian period, the Anatolian metal trade was effectively dominated by the Hittites and the Hurrians. These peoples now controlled the Mediterranean ports, while the Kassites controlled the river route south to the Persian Gulf.
The Middle Assyrian kingdom was well organized, and in the firm control of the king, who also functioned as the High Priest of Ashur, the state god. He had certain obligations to fulfill in the cult, and had to provide resources for the temples. The priesthood became a major power in Assyrian society. Conflicts with the priesthood are thought to have been behind the murder of king Tukulti-Ninurta I.
The main Assyrian cities of the middle period were Ashur, Kalhu (Nimrud) and Nineveh, all situated in the Tigris River valley. At the end of the Bronze Age, Nineveh was much smaller than Babylon, but still one of the world's major cities (population ca. 33,000). By the end of the Neo-Assyrian period, it had grown to a population of some 120,000, and was possibly the largest city of that time. All free male citizens were obliged to serve in the army for a time, a system which was called the ilku-service. The Assyrian law code, notable for its repressive attitude towards women in their society, was compiled during this period.