公元前15世紀末葉以後，亞述又開始強大起來，進入中亞述時期，但當時的形勢對亞述來說十分不利，小亞細亞的赫梯王國和新王國時期的埃及都在敘利亞擴張自己的勢力，從而阻斷了亞述嚮西的擴張。然而亞述仍不斷尋找擴張機會，先是打敗了兩河流域南部的加喜特人，將亞述的邊界嚮南推進，又兩度同米坦尼作戰，迫使米坦尼與自己的競爭對手埃及結盟，然而亞述最後還是殲滅了米坦尼，占其所有國土。公元前13世紀初，亞述甚至威脅到赫梯的安全，使赫梯也同樣嚮自己的競爭對手埃及結盟。亞述也曾西徵腓尼基，自赫梯滅亡後，中亞述王國曾一度統一兩河流域。但其後受到阿拉美亞人入侵，令亞述國力受挫。
商業方面，由於赫梯強大，亞述已不能再在小亞細亞建立新的商業殖民地，亞述商人不得不將資本轉入國內。然而，亞述本身生産力不是非常發達，回流商業資本無法轉入生産過程，於是轉成了高利貸資本，侵入農村，導致貧富懸殊日益嚴重，小生産者喪失土地，甚至遭到債務奴役。在“中期亞述法典”中有反映了這種情況，此法典現存九表，荊三表保存較完整，第一表是有關財産關係的，其中涉及土地轉讓的條款甚多；第二表則與債務及債務奴役有關，當中記載債務奴役沒有年限。在這時留下的私法文書中，也有不少關於土地買賣的契約，反映了商品貨幣關係深入農村的情況。
政治方面，中亞述時期階級矛盾尖銳，亞述的王權相對加強，並采用了君主專製的統治方式。在亞舒爾烏裏巴特一世統治時期（公元前1365－1330年），第一次在官方名表和印章上自稱為“亞述國之王”，並與埃及法老稱為兄弟。在阿達德·尼拉裏一世時，國王更身兼名年官一職，徹底成為專製君主。
中亞述時期君主
* 伊裏巴阿達德一世 前1392年-前1366年
* 亞述路巴裏特一世 前1365年-前1330年
* 恩利爾尼拉裏 前1330年-前1319年
* 阿裏剋-登-伊利 前1319年-前1308年
* 阿達德尼拉裏一世 前1308年-前1275年
* 薩爾瑪那薩爾一世 前1275年-前1245年
* 圖庫爾蒂-尼努爾塔一世 前1245年-前1208年
* 亞述納迪納普利 前1207年-前1204年
* 亞述尼拉裏三世 前1203年-前1197年
* 恩利爾-庫杜裏-烏蘇爾 前1197年-前1193年
* 尼努爾塔-阿帕爾-伊庫爾 前1192年-前1180年
* 亞述-丹一世 前1179年-前1133年
* 亞述雷什伊希一世 前1133年-前1116年
* 提格拉特帕拉沙爾一世 前1116年-前1077年
* 阿沙裏德-阿帕爾-伊庫爾 前1077年-前1074年
* 亞述貝爾卡拉 前1074年-前1057年
* 沙姆希阿達德四世 前1057年-前1050年
* 亞述那西爾帕一世 前1050年-前1032年
* 薩爾瑪那薩爾二世 前1031年-前1020年
* 亞述尼拉裏四世 前1020年-前1016年
* 亞述拉比二世 前1016年-前973年
* 亞述雷什伊希二世 前973年-前967年
* 提格拉特帕拉沙爾二世 前967年-前935年
* 亞述-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.