Formed in 1949, the CAAC Airlines, was an all-encompassing organisation responsible for civil aviation in China as it was tasked with passenger transport, resource development and survey work, air traffic control, aircraft maintenance and personnel training. The decentralisation decision would result in numerous regional airlines, with four main carriers to be responsible for the majority of international and domestic air traffic: Air China, China Southern Airlines, China Eastern Airlines and China Southwest Airlines. 

In 1988, the CAAC granted its seven regional divisions, among which was the Guangzhou Regional Administration. China Southern Airlines began flying under its own name and livery in February 1991. At this time, the aircraft operated were Antonov An-24, Boeing 737 and Boeing 757, along with helicopters and agricultural aircraft, all inherited from the former CAAC Airlines. 

In 1991, it introduced more modern types such as the Boeing 737-300/500 and in 1992 the Boeing 767-300ER joined the fleet. In December 1992, the airline placed an order for six Boeing 777s.The airline completed its decentralisation from CAAC when it gained independence on 10 October 1993. During the airline's early years, the carrier was the dominant domestic carrier. Owing to Air China's status as the country's flag carrier, the airline was entitled to extensive international service rights, with China Eastern and China Southern’s international networks confined to mainly East Asia and within Asia, respectively. 

Like other Chinese carriers, China Southern was subjected to CAAC's exclusive right to grant operating rights for every prospective route. Starting in the mid-1990s, China Southern sought to expand its international reach beyond Asia. In December 1995, the Chinese and US governments signed an aviation agreement that would allow the commencement of non-stop air services between the two countries. After having been granted the right to establish services to Amsterdam in early 1996, the airline started Guangzhou– Beijing–Amsterdam, its first long-haul route, in November 1996. The following year, the carrier commenced non-stop trans-Pacific services to Los Angeles, as well as services to Brisbane. 

The start of European and American services coincided with the arrival of the Boeing 777s, the first of which was delivered in late December 1995. 

Although there was considerable resistance to CAAC's call to rationalise the industry, in July 2000, the administrative body announced that the ten airlines under its direct management will be merged into three airline groups, revolving around Air China, China Eastern Airlines and China Southern itself. 

Within a month, China Southern had started absorbing Zhengzhou based Zhongyuan Airlines, which at the time operated five Boeing 737s and two Xian Y-7 turboprops. The carrier would later merge with Shenyang based China Northern Airlines and Urumqi-based Xinjiang Airlines to form China Southern Air Holding Co., a process that took more than two years to complete. Consequently, China Southern's fleet expanded from some 140 aircraft to over 210. The takeovers meant that the carrier became the main airline at Shenyang and Urumqi. As a result, China Southern Airlines became one of the "Big Three" carriers in the country. 

Below were some of the airlines which were absorbed by China Southern in 2000 to create the "big three" airlines in China: Air China, China Eastern and China Southern itself. 

With the mergers and new acquisitions, China Southern expanded its fleet and it incorporated new types like the Airbus A300-600R, ATR 72-500, Embraer ERJ-145 or the McDonnell  Douglas MD-90-30. However many of this were retired as soon as 2011 as more modern types arrived. Since then, it has successively taken over shareholding stocks and joined the equity in numerous other Chinese carriers, including being the major shareholder of Xiamen Airlines (55%) and Chongqing Airlines (60%); it also invested in Sichuan Airlines (39%). Amidst the major consolidation of the airline industry, China Southern in April 2000 started dedicated cargo services from Shenzhen using a Boeing 747-200F (which was quickly upgraded to the Boeing 747-400F) . 

In July 2000, routes to Sydney and Melbourne were added. In September 2003, China Southern signed a purchase agreement for four Airbus A330-200s, to be delivered from 2005. China Southern became the first mainland Chinese A330 operator with the delivery of the first example February 2005. China Southern followed up in September 2005 with a further order for eight A330-300s and two A330-200s.

On 27 January 2011, China Southern Airlines was awarded a four-star ranking by Skytrax. Then another milestone on 17 October 2011, China Southern Airlines made its first flight with the Airbus A380. Initially, the airline deployed the A380s on domestic routes, flying between Guangzhou, Beijing, Shanghai and Hong Kong. Then for international flights, the A380 was deployed on Guangzhou-Los Angeles services. Early A380 operations were unprofitable and the aircraft, underutilised; services to Sydney were thus launched in October 2013.