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.

Nevertheless, the airline planned to double its fleet of 67 aircraft. In April 1996, China Southern placed an order for 10 Airbus A320s; the delivery of the first aircraft, and China Southern's first Airbus, was made in 1997.

The end of the 1990s was a period of consolidation for the Chinese airline industry. Initially, China Southern looked to acquire several smaller nonprofitable domestic carriers. Among the deals was the purchase of 60% shares of Guizhou Airlines.

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.

China Southern placed several landmark widebody-aircraft orders from Airbus and Boeing, in January 2005. The carrier became the first (and so far the only) Chinese carrier to commit to the Airbus A380 double-deck aircraft. On the same month, China Southern, also placed a bulk order for 60 Boeing 787s. In 2006 and 2007, China Southern Airlines confirmed another order of Boeing 737-700s and Boeing 737-800s. As well it ordered Airbus A320 family aircraft and more A330. The deliveries would continue through 2010.

Following two years of negotiations which had started in August 2004, China Southern officially joined the Sky Team alliance on 15 November 2007, becoming the eleventh carrier to join the grouping and the first mainland Chinese carrier to join an airline alliance.

Earlier during the month, the CAAC had approved the temporary operations of charter flights between mainland China and Taiwan. Then in July 2008, a China Southern Airlines Airbus A330 landed in Taipei on a regular flight. The governments of China and Taiwan had both agreed to allow direct flights across the Taiwan Strait, ending six decades of limited air travel between the two sides.

During 2009, China Southern Airlines remodelled its strategy from a point to point hub to a full hub and spoke carrier, which had been proofed successful. Along with that, the airline has rapidly expanded its international market share, particularly in Australia. On 21 January 2010, China Southern Airlines announced an order for an additional 20 A320-200s. In November 2010, China Southern Airlines signed an agreement with Airbus for the purchase of six A330s and 30 more A320s–200. On 11 January 2011, China Southern Airlines announced a lease for 10 Embraer E-190, set to be delivered from the second half of 2011.

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.

While China Southern, like the other "Big Three" Chinese carriers, had been expanding rapidly since 2000, much of their activities had been focused on the domestic market, the carrier then shifted its outlook overseas in order to sustain growth. Owing to the location of its hub at Guangzhou, the airline concentrated its international expansion on Australasia. In June 2012, with the inauguration of services from Guangzhou to London-Heathrow, the airline started marketing its services connecting Europe and Australia as the "Canton Route” The carrier had added cities such as Auckland, Istanbul, Perth and Vancouver to its route map.

During May–June 2012, China Southern Airlines has recruited Dutch flight attendants to serve the First and Business class sections for flights from Guangzhou to Amsterdam and deployed the A380 on the route. The first Boeing 787-8 was handed over to China Southern in June 2013, becoming the first Chinese carrier to take delivery of the Boeing 787 Dreamliner, which will be used as part of its international expansion plans.

In February 2014, China Southern took delivery of its first of 10th Boeing 777- 300ERs ordered, and which is to be operated on the new North American routes. In April 2017, in an effort to facilitate its rapid international expansion, China Southern ordered 20 Airbus A350-900 aircraft. The Airbus A350s would start to be delivered between 2019 and 2022.